Apo B-secretion/MTP inhibitory amides

ABSTRACT

This invention is directed to compounds of formula (I) or the stereoisomers, pharmaceutically acceptable salts and hydrates thereof. The compounds are Apo B/MTP inhibitors and are useful in the treatment of various disorders and conditions such as atherosclerosis, pancreatitis, obesity, hypercholesteremia, hypertriglyceridemia, hyperlipidemia, and diabetes. The compounds of this invention are also useful in combination with other pharmaceutical agents including cholesterol biosynthesis inhibitors and cholesterol absorption inhibitors,especially HMG-CoA reductase inhibitors and HMG-CoA synthase inhibitors; HMG-CoA reductase gene expression inhibitors; CETP inhibitors; bile acid sequestrants; fibrates; cholesterol absorption inhibitors; ACAT inhibitors, squalene synthetase inhibitors, ion-exchange resins, anti-oxidants and niacin. This invention is also directed to intermediates and processes useful in the preparation of compounds of formula (I) ##STR1##

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is the National Stage filing under 35 U.S.C. §371 basedon PCT/IB97/01368, filed internationally on Nov. 3, 1997, which claimspriority from U.S. Provisional Application No. 60/032,307, filed Nov.27, 1996.

FIELD OF THE INVENTION

This invention relates to compounds which are inhibitors of microsomaltriglyceride transfer protein (MTP) and/or apolipoprotein B (Apo B)secretion and which are, accordingly, useful for the prevention andtreatment of atherosclerosis and its clinical sequelae, for loweringserum lipids, and in the prevention and treatment of related diseases.The invention further relates to pharmaceutical compositions comprisingthese compounds and to methods of treating atherosclerosis, obesity, andrelated diseases and/or conditions with said compounds, either alone orin combination with other medicaments, including lipid lowering agents.Further still, the invention relates to certain processes andintermediates related thereto which are useful in the preparation of thecompounds of the instant invention.

BACKGROUND OF THE INVENTION

Microsomal triglyceride transfer protein catalyzes the transport oftriglyceride, cholesteryl ester, and phospholipids and has beenimplicated as a putative mediator in the assembly of Apo B-containinglipoproteins, biomolecules which contribute to the formation ofatherosclerotic lesions. Specifically, the subcellular (lumen of themicrosomal fraction) and tissue distribution (liver and intestine) ofMTP have led to speculation that it plays a role in the assembly ofplasma lipoproteins, as these are the sites of plasma lipoproteinassembly. The ability of MTP to catalyze the transport of triglyceridebetween membranes is consistent with this speculation, and suggests thatMTP may catalyze the transport of triglyceride from its site ofsynthesis in the endoplasmic reticulum membrane to nascent lipoproteinparticles within the lumen of the endoplasmic reticulum.

Compounds which inhibit MTP and/or otherwise inhibit Apo B secretion areaccordingly useful in the treatment of atherosclerosis and otherconditions related thereto. Such compounds are also useful in thetreatment of other diseases or conditions in which, by inhibiting MTPand/or Apo B secretion, serum cholesterol and triglyceride levels may bereduced. Such conditions may include, for example, hypercholesterolemia,hypertriglyceridemia, pancreatitis, and obesity; andhypercholesterolemia, hypertriglyceridemia, and hyperlipidemiaassociated with pancreatitis, obesity, and diabetes. For a detaileddiscussion, see for example, Wetterau et al., Science, 258, 999-1001,(1992), Wetterau et al., Biochem. Biophys. Acta., 875, 610-617 (1986),European patent application publication No. 0 584 446 A2, and Europeanpatent application publication No. 0 643 057 A1 the latter of whichdiscloses certain compounds of the generic formulae ##STR2## which haveutility as inhibitors of MTP.

SUMMARY OF THE INVENTION

The instant invention relates to compounds which are Apo B-secretion/MTPinhibitors represented by the structural formula (I), including thestereoisomers and the pharmaceutically acceptable salts and hydratesthereof, ##STR3## wherein G is selected from: (a) a phenyl orheterocyclic ring wherein said heterocyclic ring contains a total offrom 3 to 14 ring atoms, wherein said heterocyclic ring incorporates atotal of from 1 to 4 ring heteroatoms selected independently fromoxygen, nitrogen, and sulfur, wherein the individual rings of saidheterocyclic ring may be independently saturated, partially saturated oraromatic, and wherein each of said phenyl or heterocyclic rings may haveoptionally from 1 to 4 substituents selected independently from halogen,hydroxy, cyano, nitro, oxo, thioxo, aminosulfonyl, phenyl, phenoxy,phenylthio, benzyl, benzoyl, benzyloxy, (C₁ -C₁₀)alkyl, (C₁-C₄)perfluoroalkyl, (C₁ -C₁₀)alkoxy, (C₁ -C₄)perfluoroalkoxy, (C₁-C₁₀)alkoxycarbonyl, (C₁ -C₁₀)alkylthio, (C₁ -C₁₀)alkylamino, di(C₁-C₁₀)alkylamino, (C₁ -C₁₀)alkylaminocarbonyl, di(C₁-C₁₀)alkylaminocarbonyl, di(C₁ -C₁₀)alkylamino(C₁ -C₁₀)alkoxy, (C₁-C₁₀)acyl, (C₁ -C₁₀)perfluoroacyl, (C₁ -C₁₀)acyloxy, (C₁ -C₁₀)acyloxy(C₁-C₁₀)alkyl, (C₁ -C₆)acylamino and (C₆ -C₆)perfluoroacylamino;

(b) --CH₂ CN, ##STR4## (d) (C₂ -C₁₂)alkyl or (C₂ -C₁₂)perfluoroalkylwherein each of said (C₂ -C₁₂)alkyl and (C₂ -C₁₂)perfluoroalkyl issubstituted optionally with from 1-3 substituents selected independentlyfrom:

(1) phenyl, halogen, nitro, cyano, hydroxy, --NR¹ R², --OCOR³, (C₁-C₄)alkoxy, (C₁ -C₄)perfluoroalkoxy, (C₁ -C₄)thioalkoxy or (C₁-C₄)perfluorothioalkoxy,

where R¹ and R² in the definition of --NR¹ R² are each selectedindependently from hydrogen, formyl, phenyl, benzyl, benzoyl, (C₃-C₈)cycloalkyl, (C₃ -C₈)cycloalkenyl, (C₁ -C₄)alkyl, (C₁-C₄)perfluoroalkyl, (C₁ -C₁₀)alkoxycarbonyl, (C₁ -C₆)acyl, (C₁-C₆)perfluoroacyl, aminocarbonyl, (C₁ -C₁₀)alkylaminocarbonyl, di(C₁-C₁₀)alkylaminocarbonyl, aminosulfonyl, (C₁ -C₄)alkylaminosulfonyl,di(C₁ -C₄)alkylaminosulfonyl, (C₁ -C₄)perfluoroalkylaminosulfonyl, (C₁-C₄)perfluoroalkylaminosulfonyl, di(C₁ -C₄)alkylsulfonyl, and (C₁-C₄)perfluoroalkylsulfonyl,

or where R¹ and R², taken together with the nitrogen atom to which theyare attached, form a saturated, partially-saturated or aromaticheterocyclic ring, wherein said heterocyclic ring contains a total offrom 3 to 14 ring atoms and incorporates optionally an additional 1 to 4ring heteroatoms selected independently from oxygen, nitrogen andsulfur, wherein said heterocyclic ring may have optionally from 1 to 4substituents selected independently from halogen, hydroxy, cyano, nitro,oxo, thioxo, aminosulfonyl, phenyl, phenoxy, phenylthio, benzyl,benzoyl, benzyloxy, (C₁ -C₁₀)alkyl, (C₁ -C₄)perfluoroalkyl, (C₁-C₁₀)alkoxy, (C₁ -C₄)perfluoroalkoxy, (C₁ -C₁₀)alkoxycarbonyl, (C₁-C₁₀)alkylthio, (C₁ -C₁₀)alkylamino, di(C₁ -C₁₀)alkylamino, (C₁-C₁₀)alkylaminocarbonyl, di(C₁ -C₁₀)alkylaminocarbonyl, di(C₁-C₁₀)alkylamino(C₁ -C₁₀)alkoxy, (C₁ -C₁₀)acyl, (C₁ -C₁₀ perfluoroacyl(C₁ -C₁₀)acylamino, (C₁ -C₁₀)acyloxy, and (C₁ -C₁₀)acyloxy, and (C₁-C₁₀)alkyl,

where R³ is selected from --NR¹ R², phenyl, (C₁ -C₁₀)alkyl, (C₁-C₄)perfluoroalkyl, (C₁ -C₆)alkoxy and (C₁ -C₆)perfluoroalkoxy,

(2) (C₃ -C₈)cycloalkyl or (C₃ -C₈)cycloalkenyl wherein each of said (C₃-C₈)cycloalkyl and (C₃ -C₈)cycloalkenyl may have optionally from 1 to 4substituents selected independently from halogen, hydroxy, cyano, nitro,oxo, thioxo, aminosulfonyl, phenyl, phenoxy, phenylthio, benzyl,benzoyl, benzyloxy, (C₁ -C₁₀)alkyl, (C₁ -C₄)perfluoroalkyl, (C₁-C₁₀)alkoxy, (C₁ -C₄)perfluoroalkoxy, (C₁ -C₁₀)alkoxycarbonyl, (C₁-C₁₀)alkylthio, (C₁ -C₁₀)alkylamino, di(C₁ -C₁₀)alkylamino,(C₁-C₁₀)alkylaminocarbonyl, di(C₁ -C₁₀)alkylaminocarbonyl, di(C₁-C₁₀)alkylamino(C₁ -C₁₀)alkoxy, (C₁ -C₁₀)acyl, (C₁ -C₁₀)perfluoroacyl,(C₁ -C₁₀)acylamino, (C₁ -C₁₀)perfluoroacylamino, (C₁ -C₁₀)acyloxy, and(C₁ -C₁₀)acyloxy(C₁ -C₁₀)alkyl, and

(3) a saturated, partially-saturated or aromatic heterocyclic ringcontaining a total of from 3 to 14 ring atoms, wherein said heterocyclicring incorporates a total of from 1 to 4 ring heteroatoms selectedindependently from oxygen, nitrogen and sulfur, wherein saidheterocyclic ring may have optionally from 1 to 4 substituents selectedindependently from halogen, hydroxy, cyano, nitro, oxo, thioxo,aminosulfonyl, phenyl, phenoxy, phenylthio, benzyl, benzoyl, benzyloxy,(C₁ -C₁₀)alkyl, (C₁ -C₄)perfluoroalkyl, (C₁ -C₁₀)alkoxy, (C₁-C₄)perfluoroalkoxy, (C₁ -C₁₀)alkoxycarbonyl, (C₁ -C₁₀)alkylthio, (C₁-C₁₀)alkylamino, di(C₁ -C₁₀)alkylamio, (C₁ -C₁₀)alkylaminocarbonyl,di(C₁ -C₁₀)alkylaminocarbonyl, di(C₁ -C₁₀)alkylamino(C₁ -C₁₀)alkoxy, (C₁-C₁₀)acyl, (C₁ -C₁₀)perfluoroacyl, (C₁ -C₁₀)acylamino, (C₁-C₁₀)perfluoroacylamino, (C₁ -C₁₀)acyloxy, and (C₁ -C₁₀)acyloxy(C₁-C₁₀)alkyl,

provided that (C₂ -C₁₂)alkyl does not include unsubstituted allyl;

(e) (C₃ -C₈)cycloalkyl or (C₃ -C₈)cycloalkenyl wherein each of said (C₃-C₈)cycloalkyl and (C₃ -C₈)cycloalkenyl may have optionally from 1 to 4substituents selected independently from halogen, hydroxy, cyano, nitro,oxo, thioxo, aminosulfonyl, phenyl, phenoxy, phenylthio, benzyl,benzoyl, benzyloxy, (C₁ -C₁₀)alkyl, (C₁ -C₄)perfluoroalkyl, (C₁-C₁₀)alkoxy, (C₁ -C₄)perfluoroalkoxy, (C₁ -C₁₀)alkoxycarbonyl, (C₁-C₁₀)alkylthio, (C₁ -C₁₀)alkylamino, di(C₁ -C₁₀)alkylamino, (C₁-C₁₀)alkylaminocarbonyl, di(C₁ -C₁₀)alkylaminocarbonyl, di(C₁-C₁₀)alkylamino(C₁ -C₁₀)alkoxy, (C₁ -C₁₀)acyl, (C₁ -C₁₀)perfluoroacyl,(C₁ -C₁₀)acylamino, (C₁ -C₁₀)perfluoroacylamino, (C₁ -C₁₀)acyloxy, and(C₁ -C₁₀)acyloxy(C₁ -C₁₀)alkyl; and

(f) --(CH₂)_(n) COR⁴, where R⁴ is selected from hydroxy, phenyl, --NR¹R², (C₁ -C₄)alkyl, (C₁ -C₄)perfluoroalkyl, (C₁ -C₄)alkoxy, (C₁-C₄)perfluoroalkoxy, (C₃ -C₈)cycloalkyl, and (C₃ -C₈)cycloalkenyl,

where n is an integer from 1 to 4.

A preferred subgroup of the compounds of formula (I) and thestereoisomers, pharmaceutically acceptable salts and hydrates thereof,includes those compounds wherein G is selected from:

(a) a phenyl or heterocyclic ring wherein said heterocyclic ringcontains a total of from 3 to 7 ring atoms, wherein said heterocyclicring incorporates a total of from 1 to 4 ring heteroatoms selectedindependently from oxygen, nitrogen, and sulfur, wherein saidheterocyclic ring may be saturated, partially saturated or aromatic, andwherein each of said phenyl or heterocyclic rings may each haveoptionally from 1 to 4 substituents selected independently from halogen,hydroxy, phenyl, benzyl, benzoyl, benzyloxy, (C₁ -C₁₀)alkyl, (C₁-C₄)perfluoroalkyl, (C₁ -C₁₀)alkoxy, (C₁ -C₄)perfluoroalkoxy, (C₁-C₁₀)alkoxycarbonyl, (C₁ -C₁₀)alkylthio, (C₁ -C₁₀)alkylamio, di(C₁-C₁₀)alkylamino, (C₁ -C₁₀)alkylaminocarbonyl, di(C₁-C₁₀)alkylaminocarbonyl, di(C₁ -C₁₀)alkylamino(C₁ -C₁₀)alkoxy, (C₁-C₁₀)acyl, (C₁ -C₁₀)perfluoroacyl, (C₁ -C₆)acylamino, (C₁-C₆)perfluoroacylamino, (C₁ -C₁₀)acyloxy, and (C₁ -C₁₀)acyloxy(C₁-C₁₀)alkyl;

(b) (C₂ -C₁₂)alkyl wherein said (C₂ -C₁₂)alkyl is substituted optionallywith from 1-3 substituents selected from:

(1) phenyl, halogen, cyano, hydroxy, --NR¹ R², --OCOR³, (C₁ -C₄)alkoxy,or (C₁ -C₄)perfluoroalkoxy,

where R³ is selected from --NR¹ R², (C₁ -C₄)alkyl and (C₁-C₄)perfluoroalkyl,

(2) (C₃ -C₆)cycloalkyl or (C₃ -C₆)cycloalkenyl wherein each of said (C₃-C₆)cycloalkyl and (C₃ -C₆)cycloalkenyl may optionally have from 1 to 4substituents selected independently from hydroxy, (C₁ -C₄)alkyl, (C₁-C₄)alkoxy, and (C₁ -C₄)alkoxycarbonyl, and

(3) a saturated, partially-saturated or aromatic heterocyclic ringcontaining a total of from 3 to 6 ring atoms, wherein said heterocyclicring incorporates a total of from 1 to 4 ring heteroatoms selectedindependently from oxygen, nitrogen and sulfur, wherein saidheterocyclic ring may have optionally from 1 to 4 substituents selectedindependently from halogen, hydroxy, phenyl, benzyl, benzoyl, benzyloxy,(C₁ -C₁₀)alkyl, (C₁ -C₄)perfluoroalkyl, (C₁ -C₁₀)alkoxy, (C₁-C₁₀)alkoxycarbonyl, (C₁ -C₁₀)alkylthio, (C₁ -C₁₀)alkylamino, di(C₁-C₁₀)alkylamino, (C₁ -C₁₀)alkylaminocarbonyl, di(C₁-C₁₀)alkylaminocarbonyl, di(C₁ -C₁₀)alkylamino(C₁ -C₁₀)alkoxy, (C₁-C₄)perfluoroalkoxy, (C₁ -C₁₀)acyl, (C₁ -C₁₀)acylamino, (C₁-C₁₀)perfluoroacylamino, (C₁ -C₁₀)acyloxy, and (C₁ -C₁₀)acyloxy(C₁-C₁₀)alkyl;

provided that (C₂ -C₁₂)alkyl does not include unsubstituted allyl,

(c) (C₃ -C₆)cycloalkyl or (C₃ -C₆)cycloalkenyl wherein each of said (C₃-C₆)cycloalkyl and (C₃ -C₆)cycloalkenyl may have optionally from 1 to 4substituents selected independently from hydroxy, (C₁ -C₄)alkyl, (C₁-C₄)alkoxy, (C₁ -C₁₀)acylamino, (C₁ -C₁₀)perfluoroacylamino and (C₁-C₄)alkoxycarbonyl; and

(d) --(CH₂)_(n) COR⁴, where R⁴ is selected from hydroxy, phenyl, --NR¹R², (C₁ -C₄)alkyl, (C₁ -C₄)perfluoroalkyl, (C₁ -C₄)alkoxy, (C₁-C₄)perfluoroalkoxy, (C₃ -C₆)cycloalkyl, and C₃ -C₆)cycloalkenyl,

where n is an integer from 1 to 4.

More particularly preferred of the compounds of formula (I) includingthe stereoisomers, pharmaceutically acceptable salts and hydratesthereof, are those compounds of the subgroup wherein G is selected from:

(a) (C₂ -C₁₂)alkyl, wherein said (C₂ -C₁₂)alkyl is substitutedoptionally with a group selected from phenyl, halogen, cyano, hydroxy,(C₁ -C₄)alkoxy, or a saturated, partially-saturated or aromaticheterocyclic ring selected from thienyl, pyrazolyl, pyrrolidinyl,pyrrolyl, furanyl, thiazolyl, isoxazolyl, imidazolyl, triazolyl,tetrahydropyranyl, pyridyl, and pyrimidyl, wherein each of saidheterocyclic rings may have optionally from 1 to 3 substitutentsselected independently from halogen, (C₁ -C₄)acyl, (C₁-C₄)perfluoroacyl, (C₁ -C₄)alkyl, (C₁ -C₄)perfluoroalkyl (C₁ -C₄)alkoxy,(C₁ -C₄)alkylaminocarbonyl, and (C₁ -C₄)acylamino;

provided that (C₂ -C₁₂)alkyl does not include unsubstituted allyl;

(b) --(CH₂)_(n) NR¹ R², where n is an integer from 2 to 4; and

(c) --(CH₂)_(n) COR⁴, where n is 1 or 2.

The following compounds of formula (I), including the stereoisomers andthe pharmaceutically acceptable salts and hydrates thereof, listedhereinbelow together with their corresponding IUPAC chemical names, areespecially preferred wherein G is selected from:

--CH₂ COOH,

{6-[(4'-Trifluoromethylbiphenyl-2-carbonyl)-amino]-3,4-dihydro-1H-isoquinolin-2-yl}-aceticacid;

--(CH₂)₄ CH₃,

4'-Trifluoromethylbiphenyl-2-carboxylicacid-(n-pentyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide;

--(CH₂)₃ OCH₃,

4'-Trifluoromethylbiphenyl-2-carboxylicacid-[2-(3-methoxypropyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide;

--(CH₂)₂ OCH₃,

4'-Trifluoromethylbiphenyl-2-carboxylicacid-[2-(2-methoxyethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide;

--(CH₂)₂ OCH₂ CH₃,

4'-Trifluoromethylbiphenyl-2-carboxylicacid-[2-(2-ethoxyethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide;

--(CH₂)₂ CN,

4'-Trifluoromethylbiphenyl-2-carboxylicacid-[2-(2-cyanoethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide;

--(CH₂)₂ OCOCH₃,

Acetic acid2-{6-[(4'-trifluoromethylbiphenyl-2-carbonyl)-amino]-3,4-dihydro-1H-isoquinolin-2-yl}-ethylester;

--(CH₂)₂ OCON(CH₃)₂,

Dimethylcarbamic acid2-{6-[(4'-trifluoromethylbiphenyl-2-carbonyl)-amino]-3,4-dihydro-1H-isoquinolin-2-yl}ethylester;

--(CH₂)₂ NH₂,

4'-Trifluoromethylbiphenyl-2-carboxylicacid-[2-(2-aminoethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide;

--(CH₂)₂ NHCOCH₃,

4'-Trifluoromethylbiphenyl-2-carboxylicacid-[2-(2-acetylaminoethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide;

--(CH₂)₂ CON(CH₃)₂,

4'-Trifluoromethylbiphenyl-2-carboxylicacid-[2-(2-dimethylcarbamoylethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide;

--CH₂ CON(CH₃)₂,

4'-Trifluoromethylbiphenyl-2-carboxylicacid-(2-dimethylcarbamoylethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide;

--CH₂ CON(CH₂ CH₃)₂,

4'-Trifluoromethylbiphenyl-2-carboxylicacid-(2-diethylcarbamoylethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide;

--(CH₂)₂ NHS(O)₂ CH₃,

4'-Trifluoromethylbiphenyl-2-carboxylicacid-[2-(2-methanesulfonylaminoethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide;

--(CH₂)₂ NHCOCF₃,

4'-Trifluoromethylbiphenyl-2-carboxylicacid-{2-[2-(2,2,2-trifluoroacetylamino)-ethyl]-1,2,3,4-tetrahydroisoquinolin6-yl}-amide;

--(CH₂)₂ NHCOCH₂ CH₃,

4'-Trifluoromethylbiphenyl-2-carboxylicacid-[2-(2-propionylaminoethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide;

--(CH₂)₂ NHCOOCH₃,

(2-{6-[4'-Trifluoromethylbiphenyl-2-carbonyl)-amino]-3,4-dihydro-1H-isoquinolin-2-yl}ethyl)carbamicacid methyl ester;

--(CH₂)₂ NHCHO,

4'-Trifluoromethylbiphenyl-2-carboxylicacid-[2-(2-formylaminoethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide;

--(CH₂)₂ NHCONHCH₃,

4'-Trifluoromethylbiphenyl-2-carboxylicacid-{2-[2-(3-methylureido)-ethyl]-1,2,3,4-tetrahydroisoquinolin-6-yl}-amide;##STR5## 4'-Trifluoromethylbiphenyl-2-carboxylic acid-{2-[2-(1-methyl-1H-pyrrol-2-yl)ethyl]-1,2,3,4-tetrahydroisoquinolin-6-yl}-amide;##STR6## 4'-Trifluoromethylbiphenyl-2-carboxylicacid-{2-[2-(2H-[1,2,4]triazol-3-yl-ethyl]-1,2,3,4-tetrahydroisoquinolin-6-yl}-amide;##STR7## 4'-Trifluoromethylbiphenyl-2-carboxylicacid-[2-(2,2-diphenylethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide;##STR8## 4'-Trifluoromethylbiphenyl-2-carboxylicacid-[2-(2-pyridin-2-yl-ethyl-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide;##STR9## 4'-Trifluoromethylbiphenyl-2-carboxylicacid-(2-phenylethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide; ##STR10##4'-Trifluoromethylbiphenyl-2-carboxylicacid-(2-piperidin-4-yl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide; and##STR11## 4'-Trifluoromethylbiphenyl-2-carboxylicacid-[2-(1-trifluoromethylacetyl-piperidin-4-yl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide.

The following selected functional group definitions and examples thereofare employed throughout the instant specification and the appendantclaims and are offered by way of illustration, and not by limitation.

The term "acyl" refers to either a straight or branched chainhydrocarbon moiety attached to a carbonyl group. Representative of suchradicals are acetyl, propionyl, butyryl, and isobutyryl, and the like.

Term "alkyl" includes both straight and branched chain hydrocarbonradicals, having optional unsaturation in the form of double ortriple-bonded carbon atoms. Representative of such radicals are methyl,ethyl, propyl, propylene, propynyl, isopropyl, isopropylene, butyl,isobutyl, isobutylene, tert-butyl, pentyl, hexyl, and so forth.

The term "alkoxy" includes a straight or branched chain hydrocarbonradical attached to an oxygen atom. Illustrative of such radicals aremethoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentoxy,hexoxy, heptoxy, and the like.

Reference to the term "halogen" is inclusive of fluorine, chlorine,bromine, and iodine unless noted otherwise.

The term "perfluoro", when used in conjunction with a specifiedhydrocarbon radical, is meant to include a substituent wherein theindividual hydrogen atoms thereof may be substituted therefor with oneor more and preferably from 1 to 9 fluorine atoms. Exemplary of suchradicals are trifluoromethyl, pentafluoroethyl, heptafluoropropyl andthe like.

Illustrative values for the term "(C₁ -C₁₀)alkoxycarbonyl" includemethoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl,butoxycarbonyl, and the like.

Illustrative values for the term "(C₁ -C₁₀)alkylthio" include thecorresponding sulfur-containing congeners of the term "alkoxy" asdefined hereinabove, including methylthio, ethylthio, propylthio,isopropylthio, butylthio, isobutylthio, pentylthio, hexylthio,heptylthio, and the like.

Illustrative values for the term "(C₁ -C₁₀)alkylamino" includemethylamino, ethylamino, propylamino, isopropylamino, butylamino,isobutylamino, and so forth.

Illustrative values for the term "di(C₁ -C₁₀)alkylamino" includedimethylamino, diethylamino, dipropylamino, di-isopropylamino, and thelike as well as N-methyl-N'-ethylamino, N-ethyl-N'-propylamino,N-propyl-N'-isopropylamino, and the like.

Illustrative values for the term "(C₁ -C₁₀)acyloxy" include acetyloxy,propionyloxy, butyryloxy, and the like and also include such radicalswhich incorporate a cyclic substituent such as benzoyloxy.

Illustrative values for the term "(C₃ -C₈)cycloalkyl" includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

Illustrative values for the term "(C₃ -C₈)cycloalkenyl" includecyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl,and the like.

It is to be understood that the term "heterocyclic ring" as employedthroughout the instant specification and appendant claims embracesheterocyclic radicals which may be either monocyclic and polycyclic innature. Exemplary of monocyclic heterocyclic ring systems are radicalssuch as furanyl, thienyl, pyrazolyl, pyrrolidinyl, pyrrolyl, thiazolyl,isoxazolyl, imidazolyl, triazolyl, tetrahydropyranyl, pyridyl,pyrimidyl, and so forth. Exemplary of polycyclic heterocyclic ringsystems are radicals such as indolyl, benzofuranyl, benzimidazolyl,quinolinyl, acridinyl, phthalazinyl, and the like.

It is to be understood further that if a carbocyclic or heterocyclicring may be bonded or otherwise attached to a designated substrate,including compound (I), through differing ring atoms without denoting aspecific point of attachment, then all possible points are intended,whether through a carbon atom or a trivalent nitrogen atom. For example,the term "pyridyl" means 2-, 3-, or 4-pyridyl, the term "thienyl" means2-, or 3-thienyl, and so forth.

The terms "treating" or "treatment" as employed herein are meant toembrace prophylactic as well as disease-remitive treatment.

The instant invention further provides pharmaceutical compositionssuitable for the treatment of conditions including atherosclerosis,pancreatitis, obesity, hypercholesterolemia, hypertriglyceridemia,hyperlipidemia and diabetes, which comprise a therapeutically effectiveamount of a compound of formula (I) shown and defined hereinabove,including the stereoisomers, pharmaceutically acceptable salts andhydrates thereof, in combination with a pharmaceutically acceptablecarrier or diluent.

The compounds of the instant invention inhibit or decrease Apo Bsecretion, likely by the inhibition of MTP, although it may be possiblethat additional mechanisms are involved. The compounds are useful intreating any of the disease states or conditions in which Apo B, serumcholesterol, and/or triglyceride levels are elevated. Accordingly, theinstant invention provides a method for inhibiting or decreasing Apo Bsecretion in a mammal in need thereof which comprises the administrationof an Apo B secretion inhibiting or decreasing amount of a compound offormula (I) or a stereoisomer, pharmaceutically acceptable salt orhydrate thereof. The invention further provides a method of treating acondition selected from atherosclerosis, pancreatitis, obesity,hypercholesterolemia, hypertriglyceridemia, hyperlipidemia, and diabeteswhich comprises administering to a mammal, especially a human, in needof such treatment a therapeutically effective amount of compound (I) ora stereoisomer, pharmaceutically acceptable salt or hydrate thereof. Apreferred subgroup of the conditions described hereinabove isatherosclerosis, obesity, hypercholesterolemia, hypertriglyceridemia,hyperlipidemia, and diabetes.

The compounds of this invention may be used in conjunction with otherpharmaceutical agents, including other lipid lowering agents. Suchagents include, for example, cholesterol biosynthesis inhibitors andcholesterol absorption inhibitors, especially HMG-CoA reductaseinhibitors and HMG-CoA synthase inhibitors; HMG-CoA reductase geneexpression inhibitors; CETP inhibitors; bile acid sequestrants;fibrates; cholesterol absorption inhibitors; ACAT inhibitors, squalenesynthetase inhibitors, ion-exchange resins, anti-oxidants and niacin. Incombination therapy treatment, the compounds of the instant inventionand the other drug therapies may be administered to mammals (e.g.humans) by conventional methods.

Specific cholesterol absorption inhibitors and cholesterol biosynthesisinhibitors are described in detail hereinbelow. Additional cholesterolabsorption inhibitors are known to those skilled in the art and aredescribed, for example, in PCT WO 94/00480.

Any HMG-CoA reductase inhibitor may be employed as the second compoundin the combination therapy aspect of the instant invention. The termHMG-CoA reductase inhibitor refers to a compound which inhibits thebiotransformation of hydroxymethylglutaryl-coenzyme A to mevalonic acidas catalyzed by the enzyme HMG-CoA reductase. Such inhibition may bedetermined readily by one of skill in the art according to standardassays (e.g., Methods of Enzymology, 1981; 71: 455-509 and thereferences cited therein). A variety of these compounds are describedand referenced hereinbelow. U.S. Pat. No. 4,231,938 (the disclosure ofwhich is hereby incorporated by reference) discloses certain compoundsisolated after cultivation of a microorganism belonging to the genusAspergillus, such as lovastatin. Also, U.S. Pat. No. 4,444,784 (thedisclosure of which is hereby incorporated by reference) disclosessynthetic derivatives of the aforementioned compounds, such assimvastatin. Additionally, U.S. Pat. No. 4,739,073 (the disclosure ofwhich is hereby incorporated by reference) discloses certain substitutedindoles, such as fluvastatin. Further, U.S. Pat. No. 4,346,227 (thedisclosure of which is hereby incorporated by reference) disclosesML-236B derivatives, such as pravastatin. In addition, EP 491,226teaches certain pyridyldihydroxyheptenoic acids, such as rivastatin.Also, U.S. Pat. No. 4,647,576 (the disclosure of which is herebyincorporated by reference) discloses certain6-[2-(substituted-pyrrol-1-yl)alkyl]-pyran-2ones such as atorvastatin.Other HMG-CoA reductase inhibitors will be known to those skilled in theart.

Any HMG-CoA synthase inhibitor may be used as the second compound in thecombination therapy aspect of this invention. The term HMG-CoA synthaseinhibitor refers to a compound which inhibits the biosynthesis ofhydroxymethylglutaryl-coenzyme A from acetyl-coenzyme A andacetoacetyl-coenzyme A, catalyzed by the enzyme HMG-CoA synthase. Suchinhibition may be determined readily by one of skill in the artaccording to standard assays (e.g., Methods of Enzymology, 1975; 35:155-160 and Methods of Enzymology, 1985; 110: 19-26 and the referencescited therein). A variety of these compounds are described andreferenced hereinbelow. U.S. Pat. No. 5,120,729 (the disclosure of whichis hereby incorporated by reference) discloses certain beta-lactamderivatives. U.S. Pat. No. 5,064,856 (the disclosure of which is herebyincorporated by reference) discloses certain spiro-lactone derivativesperpared by culturing the microorganism MF5253. U.S. Pat. No. 4,847,271(the disclosure of which is hereby incorporated by reference) disclosescertain oxetane compounds such as11-(3hydroxymethyl-4-oxo-2-oxetayl)-3,5,7-trimethyl-2,4-undecadienoicacid derivatives. Other HMG-CoA synthase inhibitors will be known tothose skilled in the art.

Any compound that decreases HMG-CoA reductase gene expression may beused as the second compound in the combination therapy aspect of thisinvention. These agents may be HMG-CoA reductase transcriptioninhibitors that block the transcription of DNA or translation inhibitorsthat prevent translation of mRNA coding for HMG-CoA reductase intoprotein. Such inhibitors may either affect transcription or translationdirectly, or may be biotransformed into compounds that have theaforementioned attributes by one or more enzymes in the cholesterolbiosynthetic cascade or may lead to the accumulation of an isoprenemetabolite that has the aforementioned activities. Such regulation isreadily determined by those skilled in the art according to standardassays (Methods of Enzymology, 1985; 110: 9-19). Several such compoundsare described and referenced below however other inhibitors of HMG-CoAreductase gene expression will be known to those skilled in the art U.S.Pat. No. 5,041,432 (the disclosure of which is incorporated herein byreference) discloses certain 15-substituted lanosterol derivatives.Other oxygenated sterois that suppress the biosynthesis of HMG-CoAreductase are discussed by E.I. Mercer (Prog. Up. Res., 1993; 32:357-416).

Any compound having activity as a CETP inhibitor can serve as the secondcompound in the combination therapy aspect of the instant invention. Theterm CETP inhibitor refers to compounds which inhibit the cholesterylester transfer protein (CETP) mediated transport of various cholesterylesters and triglycerides from high density lipoprotein (HDL) to lowdensity lipoprotein (LDL) and very low density liprotein (VLDL). Avariety of these compounds are described and referenced hereinbelowhowever other CETP inhibitors will be known to those skilled in the artU.S. Pat. No. 5,512,548 (the disclosure of which is incorporated hereinby reference) discloses certain polypeptide derivatives having activityas CETP inhibitors, while certain CETP-inhibitory rosenonolactonederivatives and phosphate-containing analogs of cholesteryl ester aredisclosed in J. Antibiot., 1996; 49(8): 815-816, and Bioorg. Med. Chem.Lett; 1996; 6: 1951-1954, respectively.

Any ACAT inhibitor can serve as the second compound in the combinationtherapy aspect of this invention. The term ACAT inhibitor refers tocompounds which inhibit the intracellular esterification of dietarycholesterol by the enzyme acyl CoA:cholesterol acyltransferase. Suchinhibition may be determined readily by one of skill in the artaccording to standard assays, such as the method of Heider et al.described in Journal of Lipid Research., 1983; 24: 1127. A variety ofthese compounds are described and referenced hereinbelow however otherACAT inhibitors will be known to those skilled in the art. U.S. Pat. No.5,510,379 (the disclosure of which is incorporated by reference)discloses certain carboxysulfonates, while WO 96/26948 and WO 96/10559both disclose urea derivatives having ACAT inhibitory activity.

Any compound having activity as a squalene synthetase inhibitor canserve as the second compound in the combination therapy aspect of theinstant invention. The term squalene synthetase inhibitor refers tocompounds that inhibit the condensation of two molecules offarnesylpyrophosphate to form squalene, a reaction that is catalyzed bythe enzyme squalene synthetase. Such inhibition is readily determined bythose skilled in the art according to standard methodology (Methods ofEnzymology 1969; 15: 393-454 and Methods of Enzymology 1985; 110:359-373 and references cited therein). A summary of squalene synthetaseinhibitors has been complied (Curr. Op. Ther. Patents (1993) 861-4).European patent application publication No. 0 567 026 A1 disclosescertain 4,1-benzoxazepine derivatives as squalene synthetase inhibitorsand their use in the treatment of hypercholesterolemia and asfungicides. European patent application publication No. 0 645 378 A1discloses certain seven- or eight-membered heterocycles as squalenesynthetase inhibitors and their use in the treatment and preventionhypercholesterolemia and fungal infections. European patent applicationpublication No. 0 645 377 A1 discloses certain benzoxazepine derivativesas squalene synthetase inhibitors useful for the treatment ofhypercholesterolemia or coronary sclerosis. European patent applicationpublication No. 0 611 749 A1 discloses certain substituted amino acidderivatives useful for the treatment of arteriosclerosis. Europeanpatent application publication No. 0 705 607 A2 discloses certaincondensed seven- or eight-membered heterocyclic compounds useful asantihypertriglyceridemic agents. PCT publication WO96/09827 disclosescertain combinations of cholesterol absorption inhibitors andcholesterol biosynthesis inhibitors including benzoxazepine derivativesand benzothiazepine derivatives. European patent application publicationNo. 0 071 725 A1 discloses a process for preparing certainoptically-active compounds, including benzoxazepine derivatives, havingplasma cholesterol and triglyceride lowering activities.

It will be appreciated by those skilled in the art that certaincompounds of the instant invention may contain anasymmetrically-substituted carbon atom and accordingly may exist in,and/or be isolated in, optically-active and racemic forms. Furthermore,some compounds may exhibit polymorphism. It is to be understood that thepresent invention encompasses any and all racemic, optically-active,polymorphic and stereoisomeric forms, or mixtures thereof, which form orforms possess properties useful in the treatment of the conditions notedhereinabove, it being well known in the art how to prepareoptically-active forms (for example, by resolution of the racemic formby recrystallization techniques, by synthesis from optically-activestarting materials, by chiral synthesis, or by chromatographicseparation using a chiral stationary phase) and how to determineefficacy for the treatment of the conditions noted herein by thestandard tests described hereinafter.

DETAILED DESCRIPTION OF THE INVENTION

In the discussion which follows, certain common chemical and proceduralabbreviations and acronyms therefor have been employed which include: Me(methyl); Et (ethyl); Bn (benzyl); THF (tetrahydrofuran); DMF(dimethylfornamide); BOC (tert-butyloxycarbonyl, a protecting group);DMAP (1,1'-dimethylaminopyridine), Ms (methanesulfonyl, mesyl); TFA(trifluoroacetic acid); Ac (acetyl); RP (reverse phase); HPLC (highperformance liquid chromatography); TLC (thin layer chromatography).

The compounds of formula (I) are most conveniently synthesized byemploying processes analogous to those known in the chemical arts forthe production of similar compounds. Such processes for the manufactureof a compound of formula (I) as defined in detail hereinabove areprovided as further features of the invention and are illustrated by thefollowing procedures in which the meanings of generic radicals are aspreviously defined unless otherwise qualified. The processes involvecoupling a compound of formula (II), ##STR12## which contributes the"western" portion of the molecule, i.e the moiety consisting of formula(II) with the hydrogen removed from the tetrahydroisoquinolinyl ringnitrogen, with a reactant which adds the "eastern", i.e. --G moiety.Reactants which furnish the eastern moiety are generally commerciallyavailable or are well precedented in the chemical literature. Thecompound of formula (II) has the chemical name"4'-trifluoromethylbiphenyl-2-carboxylicacid-(1,2,3,4-tetrahydroisoquinolin-6-yl)-amide" and is referred tohereinafter as simply "compound (II)" for the sake of convenience. Thewestern portion of the molecule which it contributes to the compounds offormula (I) is usually known as the6-[(4'-trifluoromethyl)biphen-2-ylcarbonylamino]-3,4-dihydro-1H-isoquinolin-2-ylmoiety, although less frequently, when named as a substitutent in acompound, this ring system may also be denoted as a 6-substituted"3,4-dihydro-1H-isoquinolin-2-yl" moiety.

An additional aspect of the instant invention provides for an acidaddition salt of compound (II). The isoquinoline ring nucleus ofcompound (II) contains an isolated basic center and may therefore forman acid addition salt with various organic and inorganic conjugateacids. For purposes of the instant invention, the expression "acidaddition salt" is intended to include but not be limited to such saltsas the hydrochloride, hydrobromide, sulfate, hydrogen sulfate,phosphate, hydrogen phosphate, dihydrogenphosphate, acetate, succinate,citrate, methanesulfonate (mesylate) and p-toluenesulfonate (tosylate)salts, as well as any hydrated or solvated forms thereof. Of these, thep-toluenesulfonate (tosylate) salt form is generally preferred.

The compound of formula (II) may be synthesized as outlined in Schemes1-4 and detailed experimental descriptions of each of these methods isdisclosed sequentially in Examples 1-4 hereinbelow. A further feature ofthe instant invention provides a preferred process including certainintermediates related thereto, for the preparation of compound (II) andthis method is outlined hereinbelow in Scheme 4.

Referring now to Scheme 1,2-(4-bromophenyl)ethylamine hydrobromide isreacted with ethyl formate in the presence of a base to formN-[2-(4-bromophenyl)ethyl]formamide (1). The formamide derivative thusproduced is then cyclized to the desired dihydroisoquinoline derivative(2) by treatment with phosphorus pentoxide in polyphosphoric acid.Treatment of the cyclized product with a hydrogen halide gas, (e.g.,hydrogen chloride) forms the hydrogen halide salt of7-bromo-3,4-dihydroisoquinoline. The hydrogen halide salt thus producedis then reduced to afford 7-bromo-1,2,3,-tetrahydroisoquinoline (3). Thereduced product is then nitrated by treatment with potassium nitrate inconcentrated sulfuric acid and the regioisomerically-pure nitratedfractions are separated to yield7-bromo-6-nitro-1,2,3,4-tetrahydroisoquinoline (4). The nitro compound(4) is then protected by functionalization of the tetrahydroisoquinolinering nitrogen atom with an appropriate protecting group. Exemplary ofsuch protecting groups for the nitrogen atom are benzyl and BOC groupsrespectively, however other protecting groups may also be employeddepending upon other remote functionalities present in the molecule andthe conditions of the preparative method involved. For a generaldescription of protecting groups and their uses, see T. W. Greene,Protective Groups in Organic Synthesis, John Wiley & Sons, New York,1991. The resulting N-protected tetrahydroisoquinoline product (5) ishydrogenated in the presence of palladium on calcium carbonate to formthe corresponding 6-amino derivative (6). The amine thus formed iscoupled with 4'-trifluoromethylbiphenyl-2-carboxylic acid or anactivated form thereof to furnish the corresponding amide derivative(7). Examples of activated forms of carboxylic acids, as well as4'-trifluoromethylbiphenyl-2-carboxylic acid, include the correspondingacid halide, an activated derivative which may be formed by reacting thefree add with an appropriate, commercially-available carbodiimide, e.g.,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) or1,1'-carbonyldiimidazole (CDI), as well as various other activated formswhich will be recognized readily by those skilled in the art. Ifdesired, the EDC may advantageously be polymer bound as disclosed inU.S. Pat. No. 5,416,193 (the disclosure of which is incorporated hereinby reference). Additionally, the activated carboxylic acid is normallyreacted in the presence of a suitable base, for example, an amine whichmay be polymer bound, such as polymer bound morpholino-polystyrene. Theabove method of activating carboxylic acids for coupling withappropriate substrates is not to be construed as being limited to thecase of 4'-trifluoromethylbiphenyl-2-carboxylic acid, but may be appliedequally to any carboxylic acid residue disclosed in the instantspecification and the appendant claims. Conventional deprotection of thefunctionalized tetrahydroisoquinoline ring nitrogen atom of (7) thenfurnishes compound (II), 4'-trifluoromethylbiphenyl-2-carboxylicacid-(1,2,3,4-tetrahydroisoquinolin-6-yl)-amide.

Alternatively, compound (II) may be synthesized by a second route asoutlined in Scheme 2. Referring now to Scheme 2,2-chloro-4-nitrobenzoicacid is treated with dimethyl malonate in the presence of base to formcompound (8). Compound (8) may then be treated with aqueous alcoholicbase to effect hydrolysis and decarboxylation to yield compound (9).Compound (9) may, if desired, be treated with acetic anhydride intoluene or other suitable solvent to furnish anhydride (10). Reductionof compound (9) or ringopening of compound (10) affords thecorresponding diol (11) which is then cyclized by treatment with mesylchloride followed by ammonia, thus affording compound (12). Compound(12) is then N-protected in a manner similar to that described in Scheme1, to yield compound (13), which, in turn, is reduced to furnish amine(6). Amine (6) is then coupled with4'-trifluoromethylbiphenyl-2-carboxylic acid or an activated formthereof as shown and described hereinabove in Scheme 1 to furnish thecorresponding amide analog (7) of compound (II). Compound (7) is thenN-deprotected as described previously to afford compound (II). ##STR13##

In an additional, alternative synthetic route, compound (II) may besynthesized as shown and described in Scheme 3. The nitro diol (11) fromScheme 2, is hydrogenated in the presence of a suitable catalyst, forexample platinum on carbon, to form the corresponding amino diol (14).The diol so produced may then be reacted with4'-trifluoromethylbiphenyl-2-carboxylic acid or an activated formthereof to afford amide (15). Cyclization of compound (15) with ammoniain the presence of a suitable catalyst in a manner similar to that shownand described in Scheme 2 furnishes compound (II). ##STR14##

The preferred synthetic route to compound (II), however, is outlinedbelow in Scheme 4. Here, the nitrated diacid (9) from Scheme 2 isreacted with benzylamine in acidic medium to furnish the cyclizedisoquinoline dione (16). This type of cyclocondensation reaction isnormally effected in a high boiling, protic solvent such as acetic acidat a temperature sufficient to induce ring-closure, usually the refluxtemperature of the solvent In the practice of the instant process,preferably an acetic acid solution of benzylamine and compound (9) isheated at reflux temperature for a period of 18 hours and the formedisoquinoline dione (16) is isolated by conventional workup.Alternatively, diacid (9) may be converted into an activated form asdescribed hereinabove and then condensed with benzylamine. A two-stepreduction furnishes the N-protected, 6-amino isoquinoline derivative(18) which is then functionalized with4'-trifluoromethylbiphenyl-2-carboxylic acid or an activated formthereof to afford the benzylated amide (19). In the initial step of thereduction process, dione (16) may be reduced to compound (17) by avariety of reducing agents including various diborane and borohydridecomplexes such as diborane/THF, diborane/DMS, sodium borohydride/borontrifluoride etherate, and the like in aprotic solvent systems such asTHF, alkyl ethers, toluene and so forth at temperatures which range fromabout 0° C. to the reflux temperature of the chosen solvent. In thepreferred mode of the instant process, compound (16) is reduced to theN-protected, 6-nitroisoquinoline derivative (17) using sodiumborohydride/boron trifluoride etherate in THF at 0° to reflux over aperiod of approximately 16 hours. In the second reductive step of theinstant process, compound (17) is reduced to amine (18). The skilledartisan will recognize readily a number of methods available for thereduction of the aromatic nitro group of compound (17) includingZn/aqueous HCl, Fe/acetic acid/water, and a diversity of catalyticmethods including hydrogenation in the presence of palladium, platinum,platinum oxide, rhenium and the like in protic or aprotic solvents athydrogen pressures ranging from 1-1,000 psi. In the practice of theinstant process, it is preferred that the reduction of compound (17) beeffected using catalytic hydrogenation in the presence of platinum oxidein THF at a hydrogen pressure of 50 psi. Compound (18) is then coupledwith 4'-trifluoromethylbiphenyl-2-carboxylic acid as described in Scheme1 to furnish amide (19). A variety of preparative methods for thedeprotection of compound (19) will be known to those skilled in the art.In the practice of the instant process, compound (19) is preferablydeprotected using palladium hydroxide on carbon in the presence ofammonium formate. The deprotection step is effected at a temperature of60° C. for a period of approximately 3 hours in a methanol/THF solventsystem. ##STR15##

The coupling processes employed in the synthesis of compounds of formula(I) begin with compound (II) and generally involve conventional methodsor minor modifications thereof. With specific reference to the compoundsof the instant invention a total of ten preparative routes were used forthe preparation of compounds of structure (I) and each of these isdescribed in general terms in Methods A-J hereinbelow. It is to beunderstood, however, that the various preparative methods disclosed inthe instant specification were chosen generally on the basis ofconvenience and not of limitation. The skilled artisan will appreciatethat many conceptually viable pathways are available for the synthesisof compounds of structure (I), including various combinations of MethodsA-J, and the exemplary schemes outlined hereinbelow are not to beconstrued as being the only possible preparative approaches.Experimental details and certain physicochemical data for each of thesynthetic methods is furnished in Examples 5-14. For each individualMethod A-J an exemplary synthesis is provided, which is followedthereafter by a listing of cognate preparations for each of thefollowing respective methods. For the compounds of structure (I)described in this section it is noted that the free base was usuallyisolated. For use in biological screens, the free base was, in mostinstances, converted into the hydrochloride salt form by conventionalmethods.

Method A

The procedure of Method A is represented by the following scheme and isessentially analogous to the route described by Abdel-Magid, et al.,Tetrahedron. Lett., 1990; 31: 5595. In Method A, an appropriatelysubstituted aldehyde is condensed with compound (II) via a reductiveamination procedure. Although a diversity of reducing agents such assodium borohydride, sodium cyanoborohydride, lithium aluminum hydride,sodium triacetoxyborohydride and other suitable borohydride reducingagents may be employed with success in the practice of Method A, sodiumtriacetoxyborohydride is usually preferred. In addition, 1.0 to 2.0equivalents of aldehyde are generally preferred. The reductive aminationprocedure of Method A may be carried out in either a protic or aproticsolvent such as methanol, ethanol, THF, or DMF. ##STR16##

The experimental details and physicochemical data of the compoundsproduced by Method A are provided in Example 5 hereinbelow. A minormodification of this method was used to synthesize several relatedderivatives and these compounds, together with representativepreparations, are also included in Example 5.

Method B

The procedure of Method B is represented by the following scheme. InMethod B, a cyclocondensation reaction involving diol (15) and anappropriately-substituted amine is effected in the presence of asuitable activating agent. Any suitable activating agent which is ableto convert the two hydroxyl moieties of (15) into reactive leavinggroups may be employed. For example, the hydroxyl groups may beconverted into their respective mesylates, tosylates, or triflates byreaction with a corresponding acid, acid halide or acid anhydride.Alternatively, the dihydroxyalkyl substituents of compound (15) may beconverted into alkyl halides. In the practice of the instant Method,mesyl chloride is generally preferred as the cyclization catalyst. Thecyclocondensation reaction of Method B is normally performed in anaprotic solvent such as THF or methylene chloride. ##STR17##

The experimental details and physicochemical data of the compoundsproduced according to Method B are provided in Example 6 hereinbelow.

Method C

The procedure of Method C is represented by the following scheme. InMethod C, compound (II) is coupled, in the presence of a base, with anappropriate G-bearing moiety activated with a leaving group (--X). Whilemany such leaving groups will be known to the skilled artisan, forpurposes of the instant invention, it is generally preferred that theleaving group be a halogen atom such as chlorine, bromine or iodine,most preferably bromine. A wide variety of organic and inorganic basesmay be used with success in this coupling reaction. However, it isgenerally preferred that an inorganic base, such as potassium carbonatebe employed. Normally, the coupling reaction of Method C is conducted inan aprotic solvent such as DMF or acetonitrile. ##STR18##

In two instances described hereinbelow, minor modifications with respectto reaction solvent and base were employed in the above couplingreaction. The experimental details and physicochemical data for thecompounds produced by Method C, including certain modifications thereto,are provided in Example 7 hereinbelow.

Method D

The procedure of Method D is represented by the following scheme. InMethod D, compound (II) is coupled with an appropriate G-bearingsubstrate via a Michael addition reaction. Such addition reactions arewell known to those skilled in the art, including the variouspermutations thereof. For a detailed discussion of the Michael additionreaction see, for example, H. O. House, Modem Synthetic Reactions, 2ndEd., W. A. Benjamin, Inc., Menlo Park, Calif., 1972). These additionreactions are normally carried out in protic solvents such as water, thelower alcohols (e.g. methanol or ethanol) or acetic acid. In the presentexample, acetic acid is generally preferred. ##STR19##

The experimental details and physicochemical data of the compoundsproduced according to Method D are provided in Example 8 hereinbelow.

Method E

The procedure of Method E is represented by the following scheme. InMethod E, an activated form of Compound 70 from Example 7 is convertedinto the corresponding amide derivative by reaction with anappropriately substituted amine. A diversity of preparative methods areknown to the skilled artisan for the amidation of carboxylic acidresidues. For example, the acid substrate may be activated in the formof an acid halide, such as an acid chloride. An alterative, preferredmethod of carboxylic acid activation comprises the formation of anactivated intermediate by the reaction of the free carboxylic acid withan appropriate carbodiimide, e.g. 1,1'-carbonyldiimidazole (CDI) or,preferably, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(EDC). Such activation methods are described in detail hereinabove.##STR20##

The experimental details and physicochemical data of the compoundsproduced according to Method E are provided in Example 9 hereinbelow.

Method F

The procedure of Method F is represented by the following scheme. In thepractice of Method F, a precursor incorporating a reducible moiety, i.e.G', is converted into compound (I). It is to be understood that a widevariety of reducible substrates may be transformed successfully usingthis method and that this procedure is no way limited to the instantexample which is illustrative for the synthesis of a compound ofstructure (I) by the reduction of a carbonyl compound. For purposes ofthe instant Method, an appropriately substituted carbonyl derivative(II') may be synthesized by treating compound (II) with a carboxylicacid or an activated form thereof. In the present case the compound,4'-trifluoromethylbiphenyl-2-carboxylicacid-[2-(thiophen-2-yl-acetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide(II') is converted into the corresponding reduced form (I) by treatmentwith an appropriate reducing agent. Reducing agents suitable for thispurpose may include, for example, sodium borohydride, lithium aluminumhydride and other suitable borohydride compounds, catalytichydrogenation, and so forth. In the instant example, sodium borohydrideis generally preferred. A solvent system compatible with otherfunctional groups which may be present and the nature of the reduciblemoiety involved will be determined readily by one of ordinary skill inthe art. Such solvents include, for example, THF, DMF, acetic acid,methanol, ethanol and the like. However, depending upon the reactivenature of the reducible moiety, certain deviations which will be wellknown to the skilled artisan, may be required from the above generalteaching. ##STR21## The related synthetic details and physicochemicaldata for the compounds produced according to Method F, includingcompound (II') are described hereinbelow in Example 10.

Method G

The procedure of Method G is represented by the following generalscheme. In Method G, Compound 67 from Example 6 is derivatized by anappropriate synthetic sequence, preferably acylation, of theN-hydroxyethyl moiety of the isoquinoline nucleus. Where applicable,such derivatiation reactions, including acylation, may be effected inthe presence of a base. For example, various organic bases such astriethylamine, pyridine, N,N'-dimethylaminopyridine, and the like may beemployed conveniently. Similarly, certain inorganic bases such as sodiumcarbonate, potassium carbonate, and the like may also be used withsuccess. In the practice of Method G, an organic base such asN,N'-dimethylaminopyridine is usually preferred. As has been notedpreviously, it is well within the ability of the skilled artisan toeffect derivatizations of the N-hydroxyethyl moiety other than theacylation transformations disclosed in Method G, and the teachings ofthe instant Method are not be construed as being limited solely thereto.##STR22## Specific values for --G will be found in Example 11 along withthe synthetic details and physicochemical data related thereto.

Method H

The complete procedure of Method H is represented in the following twoschemes.

In Step 1 of Method H, Compound 49 from Example 6 is hydrolyzed to thefree N-aminoethyl Compound 94. In the practice of Method H. Compound 94is most conveniently isolated in the form of the free base, however oneskilled in the art will appreciate that a wide variety of acid additionsalts may be formed with this substrate, if desired. Such acid additionsalt forms may be formed as described hereinbelow.

Step 1 ##STR23## Step 2 ##STR24##

In Step 2 of Method H, the N-aminoethyl moiety of the isoquinoline ringnucleus of Compound 94 is derivatized in an appropriate syntheticsequence, preferably amidation. The N-aminoethyl moiety of Compound 94may be amidated with a wide variety of reagents which may includecarboxylic acids, acid halides, acid anhydrides, isocyanates,isothiocyanates and similar reactants which will be well known to thoseskilled in the art. The amidation procedures of Method H may be effectedwith or without the presence of a base. Furthermore, an activating agentsuch as 1,1'-carbonyldiimidazole (CDI) or1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) may beemployed where appropriate. It is well within the purview of the skilledartisan to effect derivatizations of the N-aminoethyl moiety other thanthe preferred amidation transformations disclosed in Method H, and theteachings of the instant Method are not to be construed as being limitedsolely thereto. In several instances minor variations in the choice ofamidating reagents were employed in the synthesis of certain compoundsby this Method and pertinent experimental details for each of thesevariations are found in Example 12.

Specific values for --G as well as synthetic details and physicochemicaldata related thereto are presented in Example 12 shown hereinbelow.

Method I

The complete procedure of Method I is represented by the following twoschemes.

In Step 1 of Method I, Compound 61 from Example 6 is deprotected tofurnish Compound 106. In the instant example, catalytic hydrogenationwas used to effect deprotection although alternate routes will be knownto the skilled artisan.

Step 1 ##STR25##

In Step 2 of Method I the piperidine ring nitrogen of Compound 106 isderivatized with an appropriate functionality, preferably an alkyl oracyl group. One skilled in the art will appreciate readily the fact thatmany analogous transformations are possible at this nitrogen atom by theintroduction of substituents other than those described herein.

Step 2 ##STR26##

For purposes of the instant invention, the preferred alkyl or acylsubstituents may be introduced by a variety of known methods. Alkylationprocedures may involve contacting the amine substrate with an alkylatingagent for example and alkyl halide or, preferably, alkylating the amineby a reductive amination procedure such as that described hereinabove inMethod A. Acylation of the amine is preferably effected by a processanalogous to that described hereinabove in Method H.

Exemplary, non-limiting values for -G as well as the synthetic detailsand physicochemical data related thereto for Method I will be found inExample 13 hereinbelow.

Method J

The procedure of Method J is shown below. Here, the cyanoethyl group ofCompound 74 from Example 7 is cyclized with formic hydrazine in thepresence of base to yield Compound 111. It will be appreciated that thenitrile moiety of Compound 74 is capable of functioning as thepenultimate precursor to other heterocyclic ring systems and the presentexample is offered only for the purpose of illustration and notlimitation. ##STR27##

The preparative details and physicochemical data related thereto forCompound 111 of Method J are found in Example 14 hereinbelow.

Conventional methods and/or techniques of purification and separationknown to those skilled in the art may be used to isolate the compoundsof this invention. Such techniques include, for example, the well-knownand established types of chromatography (such as HPLC, columnchromatography using common adsorbents such as silica gel, and thinlayer chromatography), recrystallization, and differential (i.e.,liquid-liquid) extraction techniques.

The compounds described herein form cationic salts such as acid additionsalts and the expression "pharmaceutically-acceptable salts" is intendedto define but not be limited to such salts as the hydrochloride,hydrobromide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate,dihydrogenphosphate, acetate, succinate, citrate, methanesulfonate(mesylate) and p-toluenesulfonate (tosylate) salts, as well as hydratedor solvated forms thereof. For many compounds polyaddition salts arefeasible and/or desirable.

The acid addition salts of the compounds of the present invention,including those of compound (II), may be prepared readily by reactingthe base forms with an appropriate conjugate acid. When the salt is of amonobasic acid (e.g., the hydrochloride, the hydrobromide, thep-toluenesulfonate, the acetate), the hydrogen form of a dibasic acid(e.g., the hydrogen sulfate, the succinate) or the dihydrogen form of atribasic acid (e.g., the dihydrogen phosphate, the citrate), at leastone molar equivalent and usually a molar excess of the acid is employed.However when such salts as the sulfate, the hemisuccinate, the hydrogenphosphate or the phosphate are desired, the appropriate andstoichiometric equivalent of the acid will generally be used. The freebase and the add are usually combined in a co-solvent from which thedesired salt precipitates, or can be otherwise isolated by concentrationof the mother liquor or by the precipitative effect obtained by theaddition of a non-solvent.

The compounds of the instant invention are orally administrable and areaccordingly used in combination with a pharmaceutically acceptablecarrier or diluent suitable to oral dosage forms. Suitablepharmaceutically-acceptable carriers include inert solid fillers ordiluents and sterile aqueous or organic solutions. The active compoundwill be present in such pharmaceutical compositions in amountssufficient to provide the desired dosage amount in the range describedbelow. Thus, for oral administration the compounds may be combined witha suitable solid or liquid carrier or diluent to form capsules, tablets,powders, syrups, solutions, suspensions and the like. The pharmaceuticalcompositions may, if desired, contain additional components such asflavorants, sweeteners, excipients and the like.

The tablets, pills, capsules, and the like may also contain a bindersuch as gum tragacanth, acacia, corn starch or gelatin; excipients suchas dicalcium phosphate; a disintegrating agent such as corn starch,potato starch, alginic acid; a lubricant such as magnesium stearate; anda sweetening agent such as sucrose, lactose or saccharin. When a dosageunit form is a capsule, it may contain, in addition to materials of theabove type, a liquid carrier such as a fatty oil.

Various other materials may be present as coatings or to modify thephysical form of the dosage unit. For instance, tablets may be coatedwith shellac, sugar or both. A syrup or elixir may contain, in additionto the active ingredient, sucrose as a sweetening agent, methyl andpropylparabens as preservatives, a dye and a flavoring such as cherry ororange flavor.

The compounds of the instant invention may also be administeredparenterally. For parenteral administration the compounds may becombined with sterile aqueous or organic media to form injectablesolutions or suspensions. Solutions or suspensions of these activecompounds can be prepared in water suitably mixed with a surfactant suchas hydroxypropylcellulose. If necessary, the aqueous solutions should besuitably buffered and the liquid diluent first rendered isotonic withsufficient saline or glucose. In this capacity, the sterile aqueousmedia employed are all readily available by standard techniques wellknown to those of ordinary skill in the art. The parenterallyadministrable preparations may also be manufactured in the form ofsterile solid compositions which can also be dissolved in sterile water,or some other sterile injectable medium immediately prior to intendeduse. Dispersions can also be prepared in sesame or peanut oil, ethanol,water, polyol (e.g., glycerol, propylene glycol and liquid polyethyleneglycol), suitable mixtures thereof, vegetable oils, N-methyl glucamine,polyvinylpyrrolidone and mixtures thereof in oils as well as aqueoussolutions of water-soluble pharmaceutically acceptable salts of thecompounds. Under ordinary conditions of storage and use, thesepreparations may contain a preservative to prevent the growth ofmicroorganisms. The injectable solutions prepared in this manner canthen be administered intravenously, intraperitoneally, subcutaneously,or intramuscularly.

The pharmaceutical forms suitable for injectable use include sterileaqueous solutions or dispersions and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions. In all cases, the form must be sterile and must be fluid tothe extent that easy syringability exists. It must be stable under theconditions of manufacture and storage and must be preserved against thecontaminating action of microorganisms such as bacteria and fungi. Theymay be sterilized, for example, by filtration through abacteria-retaining filter, by incorporating sterilizing agents into thecompositions, or by irradiating or heating the compositions where suchirradiating or heating is both appropriate and compatible with the drugformulation.

Additional pharmaceutical formulations may include, inter alia,suppositories, sublingual tablets, topical dosage forms and the like andthese may be prepared according to methods which are commonly acceptedin the art.

The dosage of a compound of the instant invention which is administeredwill generally be varied according to principles well known in the arttaking into account the severity of the condition being treated and theroute of administration. In general, a compound will be administered toa warm blooded animal (such as a human) so that an effective dose,usually a daily dose administered in unitary or divided portions, isreceived, for example a dose in the range of about 0.1 to about 15 mg/kgbody weight, preferably about 1 to about 5 mg/kg body weight. The totaldaily dose received will generally be between 1 and 1000 mg, preferablybetween 5 and 350 mg. The above dosages are exemplary of the averagecase; there can, of course, be individual instances where higher orlower dosage ranges are merited, and such deviations are within thescope of this invention.

The compounds of the instant invention are active as determined in thefollowing biological screens.

The activity of a compound according to the invention can be assessed bymeasuring inhibition of Apo B secretion in HepG2 cells.

HepG2 cells are grown in Dulbecco's Modified Eagles Medium plus 10%fetal bovine serum (growth medium; Gibco) in 96-well culture plates in ahumidified atmosphere containing 5% carbon dioxide until they areapproximately 70% confluent A compound to be tested is dissolved at10-20 mM in dimethyl sulfoxide which is then diluted to 1 mM in growthmedium. Serial 1:1 dilutions of this stock are made in growth medium and100 ml of each are added to separate wells of a 96-well culture platescontaining HepG2 cells. Twenty four hours later, growth medium iscollected and assayed by specific ELISA for Apo B and, as a corol, ApoAl concentrations. Inhibitors are identified as compounds that decreaseApo B secretion into the medium without affecting the secretion ofapoAl. The ELISA for Apo B is performed as follows. Monoclonal antibodyagainst human Apo B (Chemicon; Temecula, Calif.) is diluted to 5 mg/mlin phosphate buffered (8.76 g/L NaCl, 0.385 g/L KH₂ PO₄, 1.25 g/L K₂HPO₄) saline/azide (PBS+0.02% Na azide) and 100 ml are added to eachwell of a 96-well plate (NUNC Maxisorb, Rochester, N.Y.). After anovernight incubation at room temperature, the antibody solution isremoved and wells are washed 3 times with PBS/azide. Non-specific siteson the plastic are blocked by incubating wells for 1-3 hours in asolution of 1% (w/v) bovine serum albumin (BSA) made in PBS/azide. 100μl of various dilutions of growth medium from the HepG2 cells or Apo Bin the form of ultracentrifugally isolated LDL (diluted in 0.004% Tween20/1% BSA in PBS/azide) are added to each well and incubated for 18hours. Wells are aspirated and washed 3 times (0.1% Tween 20 in PBS)prior to adding 100 ml of a 1/1000 dilution of the secondary antibody,goat anti-human Apo B (Chemicon). After a 3 hr incubation at roomtemperature, this solution is aspirated and the wells are again washed 3times as above. 100 ml of a 1:1600 dilution (in PBS/1% BSA/2 mM MgCl₂)of rabbit antigoat IgG conjugated to alkaline phosphatase (Sigma; St.Louis, Mo.) are then added to each well and incubated for 1 hr at roomtemperature. After aspirating, the wells are washed 4 times as above and100 ml of 1 mg/ml p-nitrophenylphosphate (pNPP; Sigma) in 25 mM sodiumbicarbonate/2 mM MgCl₂, pH 9.5, are added to each well and incubated for20-30 minutes and then the reaction is terminated by the addition of 50ml of 0.2N NaOH. Absorbance of each well is read at 405 nm and thebackground at 650 nm is subtracted. Apo B concentration is calculatedfrom a standard curve constructed from purified LDL standards that arerun in parallel in the same assay. Apo Al is measured in an analogousmanner except that antibodies for Apo Al (Chemicon) are used in place ofthe antibodies for Apo B and antigen incubation is at 37° instead ofroom temperature.

Activity can also be confirmed if a test compound inhibits MTP activitydirectly.

Inhibition of MTP activity by a compound may be quantitated by observingthe inhibition of transfer of radiolabeled triglyceride from donorvesicles to acceptor vesicles in the presence of soluble human MTP. Theprocedure for preparing MTP is based on the method of Wetterau andZilversmit (Biochem. Biophys. Acta (1986) 875: 610). Briefly, humanliver chunks, frozen at -80° C., are thawed on ice, minced, and rinsedseveral times with ice cold 0.25 M sucrose with all subsequent stepsbeing performed on ice. A 50% homogenate in 0.25 M sucrose is preparedusing a Potter-Elvehjem Teflon pestle. The homogenate is diluted 1:1with 0.25 M sucrose and centrifuged at 10,000×g for 20 min at 4° C. Thepellet is resuspended in sucrose and recentrifuged at 10,000×g for 20min. The supernatants are combined and the microsomes pelleted bycentrifugation at 105,000×g for 75 min. The supernatant is discarded andthe microsomal pellet is suspended in a minimal volume of 0.25 Msucrose, diluted to 3 ml per gm starting liver weight with 0.15 MTris-HCl pH 8.0. This suspension is divided into 12 fractions, andcentrifuged at 105,000×g for 75 min. The supernatants are discarded andthe microsomal pellets are stored frozen at -80° C. until needed. Forpreparation of MTP prior to performing the assay, a thawed pellet issuspended in 12 ml of cold 50 mM Tris-HCl, 50 mM KCl, 5 mM MgCl, pH 7.4and 1.2 ml of a 0.54% deoxycholate (pH 7.4) solution is added slowlywith mixing to disrupt the microsomal membrane. After a 30 minincubation on ice with gentle mixing, the suspension is centrifuged at105,000×g for 75 min. The supernatant, containing the soluble MTPprotein, is dialyzed for 2-3 days with 4 changes of assay buffer (150 mMTris-HCl, 40 mM NaCl, 1 mM EDTA, 0.02% NaN3, pH 7.4). The human liverMTP is stored at 4° C. and diluted 1:5 with assay buffer just beforeuse. MTP preparations show no notable loss of transfer activity withstorage up to 30 days.

Liposomes are prepared under a nitrogen atmosphere by the roomtemperature, bath sonication of a dispersion of 400 mM eggphosphatidylcholine (PC), 75 mM bovine heart cardiolipin, and 0.82 mM[¹⁴ C]-triolein (110 Ci/mol) (NEN; Boston, Mass.) in assay buffer. Thelipids in chloroform are added in the proper amounts and dried under anitrogen stream before hydrating with assay buffer. Acceptor liposomesare also prepared under a nitrogen atmosphere by the room temperaturebath sonication of a dispersion of 1.2 mM PC, 2.3 mM triolein and 30 pM[³ H]-PC (50 Ci/mol) (NEN; Boston, Mass.) in assay buffer. The donor andacceptor liposomes are centrifuged at 160,000×g for 2 hrs at 7° C. Thetop 80% of the supernatant, that contains small unilamellar liposomes,is carefully removed and stored at 4° C. until required for subsequentuse in the transfer assays.

MTP activity is measured using a transfer assay which is initiated bymixing donor and acceptor vesicles together with the soluble MTP and acompound to be tested. To 100 ml of either a 5% BSA (control) or 5% BSAcontaining the test compound, are added 500 ml assay buffer, 100 mldonor liposomes, 200 ml acceptor liposomes and 100 ml of diluted MTPprotein. After incubabon at 37° C. for 45 min., triglyceride transfer isterminated by adding 500 ml of a 50% (w/v) DEAE cellulose suspension inassay buffer. Following 4 min of agitation, the donor liposomes, boundto the DEAE cellulose, are selectively sedimented using low speedcentrigation. An aliquot of the supernatant containing the acceptorliposomes is counted and the ³ H and ¹⁴ C counts are used to calculatethe percent recovery of acceptor liposomes and the percent triglyceridetransfer using first order kinetics. Inhibition of triglyceride transferby test compound is manifest as a decrease in ¹⁴ C radioactivitycompared to controls where no test compound is present.

Activity of a test compound as an MTP inhibitor may also be demonstratedin vivo according to the following assay:

Male mice (20-30 g.; various strains) are dosed by oral gavage (0.25ml/25 g. body weight) with the test compound in the form of a suspensionin an aqueous 0.5% methyl cellulose solution. Compound solutions aredosed either multiple times over several days or, alternatively, once 90minutes before the mice are sacrificed and blood is collected for thepreparation of serum. The serum is assayed for triglyceride andcholesterol concentration using commercial enzymatic assays(Triglyceride G: Wako Fine Chemicals; Edgewood, N.Y. and cholesterol HP;Boeringer Mannheim, Indianapolis, Ind.). Compounds which are MLTPinhibitors are identified by their ability to lower serum triglyceridesas compared to control mice dosed solely with vehicle.

The present invention is illustrated by the following Examples. However,it is to be understood that these Examples are offered by way ofillustration and are not to be construed as limiting in any way.

EXAMPLE 1

The following synthetic examples are illustrative of those proceduresshown and described hereinabove for the sequential preparation ofcompounds 1-7 and (II) of Scheme 1. The numbers shown in parenthesisfollowing the name of each tide compound correspond to the respectivecompound numbers in Scheme 1.

N-[2-(4-Bromo-phenyl)ethyl]-formamide (1)

500 g (1.78 mol) of 2-(4-Bromo-phenyl)ethylamine hydrobromide, 1 liter(12.4 mol) of ethyl formate and 248 mL (1.78 mol) of triethylamine werecombined and heated to reflux for 3 hrs. The reaction was treated with 1liter each of deionized water and ethyl acetate. The organic layer wasseparated and washed with 1 liter each of water and brine. The organiclayer was dried over anhydrous magnesium sulfate, filtered andconcentrated to yield 378 g of a solid.

MS (Cl): 245 (M+NH₄ ⁺)

7-Bromo-3,4dihydro-isoquinoline hydrochloride (2)

In a 12 liter three neck round bottom flask, 4 kg of potyphosphoric addwas heated to 150° C. and stirred. To the stirring polyphosphoric acidwas added 530 g (3.75 mol) of phosphorus pentoxide in three portions ofapproximately 176.7 g each. Once the phosphorus pentoxide had dissolved,378 g (1.66 mol) of N-[2-(4-bromo-phenyl)ethyl]-formamide was added. Thereaction temperature was then raised to 200° C. and maintained for twohours. At this point, the reaction temperature was allowed to cool to160° C. and poured onto 16 liters of ice. The mixture was stirred for0.5 hours, basified to pH 12 with 10N sodium hydroxide solution and thenextracted three times with 3 liters of methylene chloride. The combinedorganic layers were washed with 1 liter of saturated sodium chloridesolution, dried over anhydrous sodium sulfate, filtered and concentratedto an oil. The oil was dissolved in 2.5 liters of methanol and saturatedwith anhydrous HCl gas. The resulting solution was concentrated to oneliter in volume and 1 liter of diethyl ether was added. The resultingprecipitate was filtered, washed with diethyl ether and air dried toyield 219 g of the title compound as a solid.

MS (Cl): 210 (M+H⁺)

7-Bromo-1,2,3,4-tetrahydroisoquinoline (3)

A total of 219 g (0.89 mol) of 7-bromo-3,4-dihydro-isoquinolinehydrochloride and 1.5 liters of water were combined and heated to 50° C.A total of 33.7 g (0.89 mol) of sodium borohydride was added in portionsover 0.5 hours during which time the temperature rose to 62° C. Thereaction was then cooled to ambient temperature and extracted threetimes with 1 liter of methylene chloride. The combined organic layerswere washed with 1 liter of saturated sodium chloride solution, driedover anhydrous sodium sulfate and concentrated to yield 173 g of an oil.

MS (Cl): 212 (M+H⁺)

7-Bromo-6-nitro-1,2,3,4-tetrahydroisoquinoline (4)

In a 5 liter three neck round bottom flask, 173 g (0.813 mol) of7-bromo-1,2,3,4-tetrahydroisoquinoline was dissolved carefully into 950mL of concentrated sulfuric add. The resulting solution was cooled to-5° C. and a solution of 82.7 g (0.816 mol) of potassium nitrate in 1liter of concentrated sulfuric add was added dropwise. After addition,the reaction was maintained at -5° C. for 15 minutes and poured onto 3liters of ice. The resulting mixture was basified to pH 14 with 50%sodium hydroxide solution. The basic solution was extracted three timeswith 1 liter of methylene chloride. The combined organic layers werewashed with 1 liter each of water and saturated sodium chloridesolution. The organic layer was dried over anhydrous sodium sulfate,filtered and concentrated to yield 201 g of an oil. The oil, preadsorbedonto silica gel, was charged onto a column of 4 kg of silica gel andeluted with a gradient of 1-5% methanol/methylene chloride. Thefractions containing product were combined and concentrated to yield 115g of a solid.

¹ H NMR (300 MHz, CDCl₃) δ7.61 (s, 1H); 7.38 (s, 1H); 4.10 (s, 2H); 3.20(t, 2H); 2.90 (t, 2H).

7-Bromo-6-nitro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butylester (5)

A 115 g (0.447 mol) sample of7-bromo-6-nitro-1,2,3,4-tetrahydroisoquinoline, 45.2 g (0.447 mol) oftriethylamine, 97.5 g (0.447 mol) of di-tert-butyl dicarbonate, 3.2liter of dioxane and 0.5 liter of water were combined and stirred atambient temperature for 1.5 hrs. The reaction was concentrated to removethe dioxane, 1 liter of saturated sodium bicarbonate was added and themixture was extracted two times with 1 liter of methylene chloride. Theorganic layer was washed with brine, dried over magnesium sulfate andconcentrated. The resulting solid was recrystallized from isopropanol toyield 118 g of a solid.

¹ H NMR (250 MHz, DMSO) δ7.89 (s, 1H); 7.81 (s, 1H); 4.58 (s, 2H); 3.56(t, 2H); 2.81 (t, 2H); 1.42 (s, 9H).

6-Amino-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester(6)

A total of 59 g (0.16 mol) of7-bromo-6-nitro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butylester, 10 g of 5% palladium on calcium carbonate and 49 g of ammoniumacetate in 1 liter of acetic acid was hydrogenated on a Parr shaker for5 hrs. The reaction was filtered, concentrated, basified to pH 12 with4N sodium hydroxide and extracted with methylene chloride. The organiclayer was washed with water and brine, dried over magnesium sulfate andconcentrated to yield 40 g of the title compound in the form of an oil.

¹ H NMR (300 MHz, DMSO) δ4.87 (s, 2H); 4.27 (s, 2H); 3.44 (t, 2H); 2.57(t, 2H); 1.39 (s, 9H).

6-[(4'-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester (7)

A 7.6 g (29 mmol) sample of 4'-trifluoromethyl-biphenyl-2-carboxylicacid, 7.1 g (29 mmol) of6-amino-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester,100 mg of DMAP and 6.1 g (32 mmol) of EDCl were reacted in 130 mL ofmethylene chloride for 12 hrs. The reaction mixture was extracted with2×150 mL 1N HCl, 2×150 mL 1N NaOH, 150 mL water, brine and thenconcentrated to yield 14 g of a beige foam.

MS (Cl): 519 (M+Na⁺)

¹ H NMR (250 MHz, CDCl₃) δ4.49 (s, 2H); 3.60 (t, 2H); 2.77 (t, 2H).

4'-Trifluoromethyl-biphenyl-2-carboxylic acid(1,2,3,4-tetrahydroisoquinolin-6-yl)-amide (II)

A total of 4 g (8 mmol) of6-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester and 6 mL (78 mmol) of trifluoroacetic acid weremixed in 60 mL of methylene chloride for 5 hrs. Methylene chloride (40mL) was added and the organic layer was washed with 3×50 mL of saturatedsodium bicarbonate followed by brine. The organic layer was dried overodium sulfate and concentrated to yield 3.1 g of solid.

MS (Cl): 397 (M+H⁺)

EXAMPLE 2

The following synthetic examples are illustrative of those proceduresshown and described hereinabove for the sequential preparation ofcompounds 8-13 of Scheme 2. The numbers shown in parenthesis followingthe name of each title compound correspond to the respective compoundnumbers in Scheme 2.

2-(Carboxy-5-nitrophenyl)malonic acid dimethyl ester (8)

A solution of 2-chloro-4-nitrobenzoic acid (75 g, 372 mmol) in dimethylmalonate (900 mL) was perfused with nitrogen for 15 min. Sodiummethoxide (48.3 g, 894 mmol) was added in one portion and the contentsexothermed to 48° C. Fifteen minutes later, copper (I) bromide (5.4 g,37 mmol) was added in one portion and the contents were heated to 70° C.for 24 hrs. The reaction, which was 70% complete as determined by NMR,was subsequently heated to 85° C. for 5 hrs to completely consume theremaining 2-chloro4-nitrobenzoic acid. Water (900 mL) was added to thecooled reaction followed by hexanes (900 mL). The aqueous layer wasseparated, toluene (900 mL) was added, the mixture was filtered andaqueous layer separated. Fresh toluene (1800 mL) was added to theaqueous layer and the biphasic mixture acidified with 6N aqueous HCl (90mL). A white precipitate formed and the contents were stirred for 18hrs. The product was filtered off and dried to give a white solid (78.1g, 70%) mp 153° C.

¹ H NMR (DMSO) δ8.37 (d, J=2 Hz, 1H), 8.30 (d, J=1 Hz, 2H), 5.82 (s,1H), 3.83 (s, 6H).

¹³ C NMR (DMSO) δ168.0, 167.3, 149.4, 137.1, 135.8, 132.5, 125.4, 123.7,54.5, 53.4.

Anal. Calcd for C₁₁ H₁₀ NO₈ : C, 48.49; H, 3.73; N, 4.71. Found: C,48.27; H, 3.72; N, 4.76.

2-Carboxymethyl-4-nitrobenzoic acid (9)

To a solution of 2-(carboxy-5-nitrophenyl)malonic acid dimethyl ester,(25.0 g, 84 mmol) in methanol (200 mL), sodium hydroxide (5 g, 125 mmol)in water (200 mL) was added. After 3 hrs the reaction was complete, themethanol was removed under vacuum, the contents cooled to 0° C. andacidified with concentrated HCl (37 mL). The aqueous layer was extractedtwice with ethyl acetate (200 mL then 100 mL), the combined organiclayers were dried with magnesium sulfate, most of the solvent removedunder vacuum, and methylene chloride (30 mL) was then added. The formedwhite solid was filtered off and dried to give 19.3 g of product as awhite solid, mp 180-82°0 C. IR(KBr) 3080, 3055, 2983, 1707, 1611, 1585,1516, 1491, 1424, 1358, 1298, 1237 cm-¹.

¹³ C NMR (DMSO) δ172.3, 167.5, 149.2, 138.8, 137.3, 132.1, 127.2, 122.4,39.8. Anal. Calcd for C₉ H₁₇ NO₆ : C, 48.01; H, 3.13; N, 6.22. Found: C,47.67; H, 3.19; N, 6.31.

2-(2-Hydroxymethyl-5-nitrophenyl)ethanol (11) through alternativeintermediate (10)

A mixture of 2-carboxymethyl-4-nitrobenzoic acid (13 g, 57.7 mmol),acetic anhydride (5.45 mL, 57.7 mmol) and toluene (130 mL) were heatedto reflux for 5 hrs. The solvent was removed under vacuum to yield6-nitro-isochroman-1,3-dione (compound (10) in Scheme 2) as a yellowsolid (10.51 g, 88%). Borane tetrahydrofuran complex (35.6 mL, 1M inTHF) was added dropwise over 40 min to a solution of6-nitro-isochroman-1,3-dione (2 g, 9.66 mmol) in THF (40 mL) at 0° C.The contents were then stirred for 18 hrs at 25° C., cooled to 0° C.,quenched with methanol (30 mL), and stirred for 1 hr. The solvents wereremoved under vacuum, ethyl acetate (30 mL) was added and the organicphase was washed with 10% aqueous hydrochloric acid. The aqueous acidiclayer was backwashed with ethyl acetate (30 mL), the combined organiclayers were dried with magnesium sulfate, and evaporated under vacuumuntil approximately 2 mL of ethyl acetate remained. This solution wasfiltered through silica gel washing with methylene chloride (30 mL) toremove impurities. The silica gel was flushed with ethyl acetate, thesolvent was removed under vacuum to give a solid which was slurried inmethylene chloride and filtered to afford the title diol as a whitesolid, 1.38 g , 73%.

2-(2-Hydroxymethyl-5-nitrophenyl)-ethanol (11)

A THF (60 mL) solution of 2-carboxymethyl-4-nitrobenzoic acid (3.0 g,13.3 mmol) was treated with borane-THF complex (53.3 mL, 53.3 mmol) over15 min at 0° C. The reaction was stirred for 18.5 hrs, quenched withTHF/water (1:1, 30 mL), water (20 mL) added and the layers separated.The aqueous layer was backwashed with THF (30 mL), the combined organicphase was washed with brine, dried with magnesium sulfate, and thesolvent removed under vacuum to give the product as a white solid (2.05g, 78%) mp 79-81° C.

IR(KBr) 3277, 3192, 2964, 2932, 1614, 1525, 1507, 1170, 1134, 1089, 1067cm-¹.

¹³ C NMR (DMSO) δ149.1, 146.6, 139.2, 127.8, 124.3, 121.3, 61.2, 60.6,34.9.

Anal. Calcd for C₉ H₁₁ NO₄ : C, 54.82; H, 5.62; N, 7.10. Found: C,54.54; H, 5.49; N, 7.07.

6-Nitro-1,2,3,4-tetrahydroisoquinoline (12)

Methanesulfonyl chloride (0.9 mL, 11.63 mmol) was added dropwise over 10min to a solution of 2-(2-hydroxymethyl-5-nitrophenyl)-ethanol (1.0 g,5.07 mmol), triethyl amine (1.8 mL, 12.9 mmol), in methylene chloride(20 mL). TLC showed the reaction to be complete after 30 min.

¹ H NMR (CD₃ Cl) δ8.17-11 (m, 2H), 7.65 (d, J=9 Hz, 1H), 5.36 (s, 2H),4.49 (t, J=6 Hz, 2H), 3.25 (t, J=6 Hz, 2H), 3.08 (s, 3H), 2.98 (s, 3H).

The reaction mixture was washed with 10% aqueous HCl, saturated aqueoussodium bicarbonate, and brine. The organic layer was dried withmagnesium sulfate, methylene chloride removed under vacuum and chasedwith THF (3×100 mL). The product (1.9 g) was employed directly in thenext step without further purification. Ammonia (50 mL) was added to thedimesylate (1.9 g) in THF (30 mL) at -78° C. The contents were warmed to24° C for 60 hrs, the excess ammonia distilled out, and solvent removedunder vacuum to give the crude product (786 mg, 82%). Toluene was added,the solution was filtered through magnesium sulfate and the solvent wasremoved under vacuum to yield 721 mg (75%) of an amber oil.

¹ H NMR (CDCl₃) δ7.97 (s, 1H), 7.95 (d, J=9 Hz, 1H), 7.15 (d, J=9 Hz,1H), 4.07 (s, 2H), 3.15 (t, J=6 Hz, 2H), 2.89 (t, J =6Hz, 2H), 1.98 (bs,1H).

6-Nitro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester(13)

To a solution of 6-nitro-1,2,3,4-tetrahydro-isoquinoline (840 mg, 4.71mmol) in methylene chloride (17 mL) containing triethylamine (0.72 mL,5.17 mmol) was added BOC-anhydride (1.44 mL, 6.26 mmol). Saturatedaqueous sodium bicarbonate was added 5 hr later, the phases separated,the organic layer dried with magnesium sulfate, and the solvent wasremoved under vacuum to give the product as a pale white solid (1.2 g,92%). mp 138-41° C.

IR(KBr) 3056, 3018, 2982, 2935,1734,1684,1612, 1522, 1399, 1236 cm-¹. ¹H

NMR (CDCl₃) δ8.04 (t, J=5 Hz, 1H), 8.01 (s, 1H), 7.26 (t, J=5 Hz, 1H),4.65 (s,2H), 3.68 (t, J=6 Hz, 2H), 2.93 (t, J=6 Hz, 2H), 1.49 (s, 9H).

6-Amino-3,4dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester(6)

The 6-nitro-3,4-dihydro-1H-isoquinoline2-carboxylic acid tert-butylester (82 mg, 0.29 mmol) in THF (2 mL) was hydrogenated with 5% Pt-C(50% water wet, 10 mg) at 50 psi for 5 hrs. The catalyst was filteredoff, the solvent was removed under vacuum and the residuechromatographed on silica with ethyl acetate/hexanes to give 42 mg (57%)of the title product.

IR(KBr) 3005, 2975, 2928, 1685, 1627, 1509, 1423, 1365, 1166 cm-¹.

¹ H NMR (CDCl₃) δ6.90 (d, J=6 Hz, 1H), 6.56 (d, J=6 Hz, 1H), 6.48 (s,1H), 4.47 (s, 2H), 3.60 (m, J=6 Hz, 4H), 2.73 (t, J=6 Hz, 2H), 1.49 (s,9H).

The product was then reacted with an activated form of4'-trifluoromethylbiphenyl-2-carboxylic acid as disclosed previously toafford N-protected tetrahydroisoquinoline (7) which was then deprotectedto furnish compound (II).

EXAMPLE 3

The following synthetic examples are illustrative of those proceduresshown and described hereinabove for the preparation of compounds 14, 15and (II) in Scheme 3. The numbers shown in parenthesis following thename of each title compound correspond to the respective compoundnumbers in Scheme 3.

2-(5-Amino-2-hydroxymethylphenyl)-ethanol (14)

Pt-C (50% water wet, 200 mg) was added to a THF (40 mL) solution of2-(2-hydroxymethyl-5-nitrophenyl)-ethanol (1.0 g, 5 mmol) and themixture was hydrogenated at 50 psi for 2 hrs. NMR showed completereaction to form 2-(5-amino-2-hydroxymethyl-phenyl)-ethanol (compound(14) in Scheme 3).

¹ H NMR (CD₃ Cl) δ7.08 (d, J=2 Hz, 1H), 6.54-6.50 (m, 2H), 4.51 (s, 2H),3.82 (t, J=6 Hz, 2H), 3.80-2.95 (bs, 4H), 2.84 (t, J=6 Hz, 2H).

4'-Trifluoromethylbiphenyl-2-carbonyl chloride

A solution of 4'-(trifluoromethyl)-2-biphenylcarboxylic acid (9.08 g, 34mmol), thionyl chloride (12 mL) and dimethylformamide (0.05 mL) washeated to reflux for 2 hrs. at which time the reaction was determined tobe complete by NMR. The excess thionyl chloride was distilled bydisplacing with toluene (56 mL). The solvent was removed under vacuum togive the title acid chloride as a white solid (9.46 g, 97%).

¹ H NMR (CDCl₃) δ8.12 (dd, J=1 Hz, J=8 Hz, 1H), 7.70-7.37 (m, 7H). ¹³ CNMR CD₃ Cl δ(CO) 168.

4'-Trifluoromethylbiphenyl-2-carboxylicacid-[3-(2-hydroxymethyl)-4-hydroxymethylphenyl)]-amide (15)

The catalyst from the Pt-C hydrogenation described above was filteredoff, triethylamine (1.4 mL, 10 mmol) was added, followed by the dropwiseaddition of a THF (10 mL) solution of the4'-trifluoromethylbiphenyl-2-carbonyl chloride (1.44 g, 5 mmol) over aperiod of 1 hr. The contents were stirred for 24 hrs, the solvent wasremoved under vacuum, and ethyl acetate (40 mL) was added. The organicphase was washed with water (2×40 mL), dried with magnesium sulfate, andevaporated under vacuum. The residue was chased with toluene (3×40 mL)and evaporated to furnish 2.11 g of a white solid which was re-pulped inmethylene chloride (21 mL) for 18 hrs., filtered, and dried to give theti product as a white solid 1.71 g (81%).

4'-Trifluoromethylbiphenyl-2-carboxylicacid-(1,2,3,4-tetrahydroisoquinolin-6-yl)-amide (II)

Methanesulfonyl chloride (0.085 mL) was added to a 0° C. solution of4'-trifluoromethyl-biphenyl-2-carboxylicacid-[3-(2-hydroxy-ethyl)-4-hydroxymethyl-phenyl]-amide (214 mg, 0.51mmol) and triethylamine (0.18 mL) in THF (8.5 mL). TLC showed completereaction after 30 min. The contents were cooled to -78° C., excessammonia was added, and the contents were stirred for 18 hrs at 25° C.The solvents were removed under vacuum, methylene chloride (10 mL) andaqueous 1N HCl were added and the contents were stirred for 1 hr. Thephases were separated and the aqueous phase was rendered alkaline withaqueous sodium hydroxide to a pH of 12. The organic phase was extractedwith methylene chloride (4×10 mL), the solvent removed under vacuum togive a white solid (108 mg) which was chromatographed on silica elutingwith 5% methanol/methylene chloride with 0.5% ammonium hydroxide. Theproduct was obtained as a white solid (40 mg, 20%).

¹ H NMR (CDCl₃) δ7.76-6.83 (m, 11H), 3.89 (s, 2H), 3.52 (d, J=7 Hz,0.5H), 3.04 (t, J=6 Hz, 2H), 2.74 (m, 0.5H), 2.66 (t, J=7 Hz, 2H), 2.27(s, 1H). ¹³ C NMR CD₃ Cl δ (aliphatic carbons only) 47.8, 43.6, 29.1.

EXAMPLE 4

The following synthetic examples are illustrative of those proceduresshown and described hereinabove for the sequential preparation ofcompounds 16-19 and (II) in Scheme 4. The numbers shown in parenthesisfollowing the name of each title compound correspond to the respectivecompound numbers in Scheme 4.

2-Benzyl-6-nitro-4H-isoquinoline-1,3-dione (16)

To a suspension of the diacid (9) (55 g, 0.244 mole) in acetic acid (550mL) was added benzylamine (28.91 g, 0.27 mole). The reaction was heatedto 115° C. for 18 hrs., cooled to 25° C., water was added (450 mL), thecontents stirred for 2 hrs., and the product filtered off as a whitesolid. The product was washed with water (400 mL) and vacuum dried togive 59.51 g (82%).

¹ H NMR (DMSO) δ8.29-8.20 (m, 3H); 7.3-7.19 (m, 5H); 5.03 (s, 2H); 4.35(s, 2H). IR 3076, 2976, 1712, 1669, 1618, 1528, 1338, 1308 cm⁻¹. Anal.Calc'd for C₁₆ H₁₂ N₂ O₄ : C, 64.83; H, 4.08; N, 9.46. Found C, 64.72;H, 3.97; N, 9.49.

2-Benzyl-6-nitro-1,2,3,4-tetrahydroisoquinoline (17)

To a suspension of sodium borohydride (2.13 g, 56.2 mmole) in THF (56mL) at 0° C. was added boron trifluoride etherate (9 mL, 73 mmole)dropwise. After stirring the contents for 1 hr., dione (16) (5.0 g, 16.9mmole) in THF (150 mL) was added at 0° C. over a period of 1.5 hr. Thecontents were warmed to 25° C. for 30 min. and then refluxed for 16 hr.The completed reaction was cooled to 0° C. and cautiously quenched withaqueous 1N sodium hydroxide (75 mL, 75 mmole) while maintaining thetemperature at approximately 9° C. The quenched reaction was stirred for30 min. at 0° C., 1 hr. at 25° C., 50° C. for 18 hrs. and then cooled to20° C. The solvents were removed under vacuum, ethyl acetate (100 mL)was added and the layers separated. The organic layer was washed withbrine, treated with sodium sulfate and the solvents removed under vacuumto afford 4.73 g of a light brown oil which was of sufficient purity toemploy in the next step.

¹ H NMR (CDCl₃) δ7.98-7.29 (m, 5H); 7.38-7.10 (m, 5H); 3.71 (m, 2H);2.99 (m, 2H); 2.82 (m, 2H). IR 3064, 2940, 2794, 1589, 1518, 1492, 1347,1315 cm⁻¹. Anal. Calc'd for C₁₆ H₁₆ N₂ O₂ : C, 71.50; H, 6.00; N. 10.44.Found C, 70.76; H, 5.99; N, 10.33.

4'-Trifluoromethylbiphenyl-2-carboxylicacid-(2-benzyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide (19) throughamine intermediate (18)

A THF (184 mL) solution of compound (17) (4.6 g, 17 mmole) with platinumoxide (230 mg) was hydrogenated for 18 hrs. at 50 psi. The catalyst wasfiltered off and platinum oxide (230 mg) was added and the hydrogenationcontinued for 72 hrs. The completed hydrogenation was filtered toprovide a THF solution of the intermediate,2-benzyl-1,2,3,4-tetrahydroisoquinolin-6-yl amine (18). Triethylaminewas added to the THF solution of (18) followed by the dropwise additionof 4'-trifluoromethylbiphenyl-2-carbonyl chloride (4.88 g., 17 mmole)from Example 3. The contents were stirred subsequently for 17 hrs. Thesolvent was removed under vacuum, water (50 mL) was added, the contentsstirred for 3 hr., the product filtered off and dried under vacuum toyield 5.93 g (71%) of compound (19) as a white solid.

4'-Trifluoromethylbiphenyl-2-carboxylicacid-(1,2,3,4-tetrahydroisoquinolin-6-yl-amide (II)

Methanol (65 mL) and THF (135 mL) were added to palladium hydroxide oncarbon (1.5 g, 50% water wet) under a nitrogen atmosphere followed byamine (19) (5.0 g, 10.3 mmole) of the previous example and ammoniumformate (6.48 g, 103 mmole). The contents were heated to 60° C. for 3hr., cooled to 25° C. and filtered. Aqueous sodium hydroxide (1N, 10 mL)was added to the filtrate, the organic solvents were removed undervacuum and water (40 mL) was added. The contents were stirred for 2 hr.and the crude product was filtered off and dried yielding 4.09 g ofsolid. This material was suspended in hexane/methylene chloride (40 mLof a 3:1 ration respectively) and stirred for 2 hrs. The pure productwas filtered off and dried to give the title compound as a white solid(3.74 g, 92%).

4'-Trifluoromethylbiphenyl-2-carboxylicacid-(1,2,3,4-tetrahydroisoquinolin-6-yl)-amide (II) tosylate salt

A 1.13 g (2.85 mmole) sample of Compound (II) was dissolved in 3 mL ofethyl acetate and p-toluenesulfonic acid (436 mg, 2.3 mmole) was added.The contents were stirred at ambient temperature for 18 hrs. and theresulting white solid was filtered off and washed with ethyl acetate.The solid product was dried under vacuum to afford 1.097 g of the titletosylate salt, mp 187° C.

¹ H NMR (250 MHz, DMSO) δ10.47 (s, 1H); 7.73-6.94 (m, 16H); 4.54 (s,2H); 3.71 (s, 2H); 2.47 (s, 2H); 2.25 (s, 3H).

The following synthetic examples are exemplary of those procedures shownand described hereinabove in Methods A-J for the synthesis of thecompounds of structure (I) shown hereinabove.

EXAMPLE 5

Compounds 20-39

The following compounds were produced by the procedure of Method Adescribed hereinabove. The following synthesis is exemplary of theprocedure of Method A.

Compound 20 ##STR28## G is

4'-Trifluoromethylbiphenyl-2-carboxylicacid-(2-phenethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide

A 400 mg (1.01 mmole) sample of compound (II), phenylacetaldehyde (121mg, 1.01 mmole), sodium triacetoxyborohydride (320 mg, 1.52 mmole) andacetic acid (61 mg, 1.01 mmole) were stirred in 10 mL of1,2-dichloroethane for 12 hrs. at ambient temperature. The reaction wasdiluted with methylene chloride, washed with 1N NaOH, water and brine.Purification was carried out with silica gel chromatography using 50%ethyl acetate/hexanes as the eluent.

MS (Cl): 501 (M+H⁺)

¹ H NMR (250 MHz, CDCl₃) δ3.65 (s, 2H); 2.91 (m, 4H); 2.87 (m, 4H).

The following compounds were synthesized in a manner analogous to thatdescribed hereinabove for Compound 20.

Compound 21

G is --CH₂ CH₃

4'-Trifluoromethylbiphenyl-2-carboxylicacid-(2-ethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide

MS (Cl): 425 (M+H⁺)

¹ H NMR (250 MHz, CDCl₃) δ3.55 (s, 2H); 2.83 (t, 2H); 2.68 (t, 2H); 2.55(q, 2H); 1.17 (t, 3H).

Compound 22

G is --(CH₂)₂ CH₃

4'-Trifluoromethylbiphenyl-2-carboxylicacid-(2-n-propyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide

MS (Cl): 439 (M+H⁺)

¹ H NMR (250 MHz, CDCl₃) d 3.55 (s, 2H); 2.82 (t, 2H); 2.67 (t, 2H);2.44 (q, 2H); 1.61 (m, 2H); 0.94 (ti 2H).

Compound 23

G is --CH₂ C(CH₃)₃

4'-Trifluoromethylbiphenyl-2-carboxylicacid-[2-(2,2-dimethylpropyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide

MS (Cl): 467 (M+H⁺)

¹ H NMR (250 MHz, CDCl₃) δ3.64 (s, 2H); 2.76 (m, 4H); 2.20 (s, 2H); 0.89(s, 9H).

Compound 24 ##STR29## G is

4'-Trifluoromethylbiphenyl-2-carboxylicacid-[2-(3-phenylpropyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide

MS (Cl): 515 (M+H⁺)

¹ H NMR (250 MHz, CDCl₃) δ3.55 (s, 2H); 2.82 (t, 2H); 2.68 (m, 4H); 2.52(t, 2H); 1.91 (m, 2H).

Compound 25

G is --CH(CH₃)₂

4'-Trifluoromethylbiphenyl-2-carboxylicacid-(2isopropyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide

MS (Cl): 440 (M+H⁺)

¹ H NMR (250 MHz, CDCl₃) δ3.65 (s, 2H); 2.87 (m, 1H); 2.80 (t, 2H); 2.72(t, 2H); 1.11 (d, 6H).

Compound 26 ##STR30## G is

4'-Trifluoromethylbiphenyl-2-carboxylicacid-(2-cyclohexyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide

MS (Cl): 479 (M+H⁺)

¹ H NMR (250 MHz, CDCl₃) δ3.71 (s, 2H); 2.79 (s, 4H); 2.45 (m, 1H); 1.92(m, 2H); 1.83 (m, 2H); 1.60 (m, 1H); 1.29 (m, 5H).

Compound 27 ##STR31## G is

4'-Trifluoromethylbiphenyl-2-carboxylicacid-[2-(tetrahydropyran-4-yl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide

MS (Cl): 481 (M+H⁺)

¹ H NMR (250 MHz, CDCl₃) δ4.04 (dd, 2H); 3.71 (s, 2H); 3.41 (t, 2H);2.80 (s, 4H); 2.62 (m, 1H); 1.82 (d, 2H); 1.70 (dt, 2H).

Compound 28

G is --(CH₂)₂ C(CH₃)₃

4'-Trifluoromethylbiphenyl-2-carboxylicacid-[2-(3,3-dimethylbutyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide

MS (Cl): 482 (M+H⁺)

¹ H NMR (250 MHz, CDCl₃) δ3.55 (s, 2H); 2.82 (t, 2H); 2.68 (t, 2H); 2.49(m, 2H); 1.49 (m, 2H); 0.93 (s, 9H).

The following compounds were synthesized by a modification of Method A.A general synthetic description and a listing of the compounds that wereprepared by this modification are as follows:

A solution of an appropriately-substituted aldehyde (7.5 μmol), compound(II) (5 μmol), acetic add 7.5 μmol), and sodium triacetoxyborohydride(10 μmol) in 300 μL of 1,2 dichloroethane was shaken for 60 hrs. atambient temperature. A 7.5 μL sample was removed and diluted with 93 μLof methanol for TLC and MS analysis. The remaining sample was evaporatedto dryness under vacuum. The crude solid was dissolved in 500 μL ofethyl acetate and washed with 300 μL of 5% sodium bicarbonate. Theorganic layer was concentrated to dryness under vacuum.

Compound 29

G is --(CH₂)₂ CH(CH₃)CH₃

4'-Trifluoromethylbiphenyl-2-carboxylicacid-[2-(3-methylbutyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide

MS (Cl): 467 (M+H⁺)

Compound 30

G is --(CH₂)₆ CH₃

4'-Trifluoromethylbiphenyl-2-carboxylicacid-(2-n-heptyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide

MS (Cl): 495 (M+H⁺)

Compound 31

G is --CH₂ COCH₃

4'-Trifluoromethylbiphenyl-2-carboxylicacid-[2-(2-oxopropyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide

MS (Cl): 453 (M+H⁺)

Compound 32

G is --CH₂ CH(CH₃)₂

4'-Trifluoromethylbiphenyl-2-carboxylicacid-(2-isobutyl-1,2,3,4-isoquinolin-6-yl)-amide

MS (Cl): 453 (M+H⁺)

Compound 33 ##STR32## G is

4'-Trifluoromethylbiphenyl-2-carboxylicacid-[2-(2,2-diphenylethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide

MS (Cl): 577 (M+H⁺)

¹ H NMR (300 MHz, CDCl₃) δ4.30 (t, 1H); 3.61 (s, 2H).

Compound 34 ##STR33## G is

4'-Trifluoromethylbiphenyl-2-carboxylicacid-{2-[2-(2,6,6-trimethylcyclohex-1-enyl)-ethyl]-1,2,3,4-tetrahydroisoquinolin-6-yl}-amide

MS (Cl): 547 (M+H⁺)

Compound 35

G is --(CH₂)₁₁ CH₃

4'-Trifluoromethylbiphenyl-2-carboxylicacid-(2-dodecyl-1,2,3,4-tetrahydoisoquinolin-6-yl)-amide

MS (Cl): 565 (M+H⁺)

Compound 36

G is --CH₂ C(CH₃)₂ CH₂ N(CH₃)₂

4'-Trifluoromethylbiphenyl-2-carboxylicacid-[2-(3-dimethylamino-2,2-dimethylpropyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide

MS (Cl): 511 (M+H⁺)

Compound 37 ##STR34## G is

4'-Trifluoromethylbiphenyl-2-carboxylicacid-[2-(3-furan-2-yl-2-methylallyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide

MS (Cl): 517 (M+H⁺)

Compound 38

G is --(CH₂)₂ CH(CH₃)SCH₃

4'-Trifluoromethylbiphenyl-2-carboxylicacid-[2-(3-methylsulfanylbutyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide

MS (Cl): 499 (M+H⁺)

Compound 39 ##STR35## G is

4'-Trifluoromethylbiphenyl-2-carboxylicacid-{2-[2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-ethyl]-1,2,3,4-tetrahydroisoquinolin-6-yl}-amide

MS (Cl): 570 (M+H⁺)

EXAMPLE 6

Compounds 40-67

The following compounds were produced by the procedure of Method Bdescribed hereinabove. The following synthesis is exemplary of theprocedure of Method B.

Compound 40

G is --(CH₂)₃ CH₃

4'-Trifluoromethylbiphenyl-2-carboxylicacid-(2-n-butyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide

Methanesulfonyl chloride (0.12 mL, 1.55 mmole) was added to a 0° C.solution of compound (15) (0.30 gm, 0.723 mmole) and triethylamine (0.25mL, 1.79 mmole) in THF (7 mL). After 30 min. TLC indicated the reactionwas complete. A total of 1.06 gm (14.4 mmole) of n-butylamine was addedand the contents were stirred for 18 hrs. at ambient temperature. Thesolvent was removed under vacuum, the residue was dissolved in methylenechloride, washed with 1N NaOH and brine, and dried over sodium sulfate.Purification of the residue obtained upon evaporation was carried out onsilica gel using a gradient of 0-8% methanol in methylene chloride asthe eluent.

MS (Cl): 453 (M+H⁺)

¹ H NMR (250 MHz, DMSO) δ3.43 (s, 2H); 2.70 (t, 2H); 2.57 (t, 2H); 2.39(t, 2H); 1.47 (m, 2H); 1.31 (m, 2H); 0.88 (t, 3H).

The following compounds were synthesized in a manner analogous to thatdescribed hereinabove for Compound 40.

Compound 41 ##STR36## G is

4'-Trifluoromethylbiphenyl-2-carboxylicacid-[2-(1-(R)-phenylethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide

MS (Cl): 501 (M+H⁺)

¹ H NMR (300 MHz, CDCl₃) δ3.75 (s, 2H); 1.45 (d, 3H).

Compound 42 ##STR37## G is

4'-Trifluoromethylbiphenyl-2-carboxylicacid-(2-phenyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide

MS (Cl): 473 (M+H⁺)

¹ H NMR (250 MHz, DMSO) δ4.29 (s, 2H); 3.48 (t, 2H); 2.82 (t, 2H).

Compound 43 ##STR38## G is

4'-Trifluoromethylbiphenyl-2-carboxylicacid-[2-(2-morpholin-4-ethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide

MS (Cl): 510 (M+H⁺)

¹ H NMR (300 MHz, DMSO) δ3.49 (s, 2H).

Compound 44

G is --CH₂ CF₃

4'-Trifluoromethylbiphenyl-2-carboxylicacid-[2-(2,2,2-trifluoroethyl-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide

MS (Cl): 479 (M+H⁺)

¹ H NMR (300 MHz, DMSO) δ3.72 (s, 2H).

Compound 45

G is --(CH₂)₂ N(CH₃)₂

4'-Trifluoromethylbiphenyl-2-carboxylicacid-[2-(2-dimethylaminoethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide

MS (Cl): 468 (M+H⁺)

¹ H NMR (300 MHz, DMSO) δ3.48 (s, 2H); 2.14 (s, 6H).

Compound 46

G is --(CH₂)₄ N(CH₃)₂

4'-Trifluoromethylbiphenyl-2-carboxylicacid-[2-(2-dimethylaminobutyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide

MS (Cl): 496 (M+H⁺)

¹ H NMR (300 MHz, DMSO) δ3.43 (s, 2H); 2.11 (s, 6H).

Compound 47

G is --(CH₂)₂ OCH₃

4'-Trifluoromethylbiphenyl-2-carboxylicacid-[2-(2-methoxyethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide

MS (Cl): 455 (M+H⁺)

¹ H NMR (300 MHz, DMSO) δ3.50 (m, 4H); 3.24 (s, 3H); 2.64 (m, 6H).

Compound 48

G is --(CH₂)₃ OH

4'-Trifluoromethylbiphenyl-2-carboxylicacid-[2-(3-hydroxypropyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide

MS (Cl): 455 (M+H⁺)

¹ H NMR (300 MHz, DMSO) δ3.47 (s, 4H).

Compound 49

G is --(CH₂)₂ NHCOCH₃

4'-Trifluoromethylbiphenyl-2-carboxylicacid-[2-(2-acetylaminoethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide

MS (Cl): 482 (M+H⁺)

¹ H NMR (250 MHz, DMSO) δ3.50 (s, 2H); 1.79 (s, 3H).

Compound 50 ##STR39## G is

4'-Trifluoromethylbiphenyl-2-carboxylicacid-[2-(2-methylallyl-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide

MS (Cl): 451 (M+H⁺)

¹ H NMR (300 MHz, DMSO) δ4.90 (s, 1H); 4.87 (s, 1H); 3.40 (s, 2H); 2.96(s. 2H); 2.72 (t, 2H); 2.54 (t, 2H); 1.70 (s, 3H).

Compound 51

G is --CH₂)₂ F

4'-Trifluoromethylbiphenyl-2-carboxylicacid-[2-(2-fluoroethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide

MS (Cl): 443 (M+H⁺)

¹ H NMR (300 MHz, DMSO) δ4.67 (t, 1H); 4.51 (t, 1H); 3.55 (s, 2H).

Compound 52 ##STR40## G is

4'-Trifluoromethylbiphenyl-2-carboxylicacid-{2-[2-(1-methyl-1H-pyrrol-2-yl)-ethyl]-1,2,3,4-tetrahydroisoquinolin-6-yl}-amide

MS (Cl): 504 (M+H⁺)

¹ H NMR (300 MHz, DMSO) δ3.55 (s, 2H); 3.51 (s, 3H).

Compound 53

G is --(CH₂)₃ N(CH₃)₂

4'-Trifluoromethylbiphenyl-2-carboxylicacid-[2-(3-dimethylaminopropyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide

MS (Cl): 482 (M+H⁺)

¹ H NMR (300 MHz, DMSO) δ3.44 (s, 2H); 2.10 (s, 6H).

Compound 54 ##STR41## G is

4'-Trifluoromethylbiphenyl-2-carboxylicacid-[2-(3,3-diphenylpropyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide

MS (Cl): 591 (M+H⁺)

¹ H NMR (300 MHz, DMSO) δ4.02 (t, 1H); 3.42 (s, 2H).

Compound 55

G is --CH₂ CN

4'-Trifluoromethylbiphenyl-2-carboxylicacid-(2-cyanomethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide

¹ H NMR (300 MHz, DMSO) δ3.90 (s, 2H); 3.60 (s, 2H).

Compound 56

G is --(CH₂)₅ CH₃

4'-Trifluoromethylbiphenyl-2-carboxylicacid-(2-n-hexyl-1,2,3,4-tetrahydroisoquiolin-6-yl)-amide

MS (Cl): 481 (M+H⁺)

¹ H NMR (300 MHz, DMSO) δ3.44 (s, 2H); 0.85 (t, 3H).

Compound 57

G is --(CH₂)₂ OCH₂ CH₃

4'-Trifluoromethylbiphenyl-2-carboxylicacid-[2-(2-ethoxyethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide

MS (Cl): 469 (M+H⁺)

¹ H NMR (300 MHz, DMSO) δ3.53 (m, 4H); 1.10 (t, 3H).

Compound 58 ##STR42## G is

4'-Trifluoromethylbiphenyl-2-carboxylicacid-(2-benzhydryl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide

MS (Cl): 563 (M+H⁺)

¹ H NMR (300 MHz, DMSO) δ3.41 (s, 2H).

Compound 59

G is --(CH₂)₃ OCH₃

4'-Trifluoromethylbiphenyl-2-carboxylicacid-[2-(3-methoxypropyl-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide

MS (Cl): 469 (M+H⁺)

¹ H NMR (300 MHz, DMSO) δ3.44 (s, 2H); 3.21 (s, 3H).

Compound 60

G is --(CH₂)₄ CH₃

4'-Trifluoromethylbiphenyl-2-carboxylicacid-(2-n-pentyl-1,2,3,4-tetrahydroisoquiolin-6-yl)-amide

MS (Cl): 467 (M+H⁺)

¹ H NMR (300 MHz, DMSO) δ3.44 (s, 2H); 0.86 (t, 3H).

Compound 61 ##STR43## G is

4'-Trifluoromethylbiphenyl-2-carboxylicacid-[2-(1-benzylpiperidin-4-yl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide

MS (Cl): 570 (M+H⁺)

¹ H NMR (250 MHz, DMSO) δ3.61 (s, 2H); 3.44 (s, 2H); 2.70 (s, 4H).

Compound 62 ##STR44## G is

4'-Trifluoromethylbiphenyl-2-carboxylicacid-[2-(2-nitrophenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide

MS (Cl): 518 (M+H⁺)

¹ H NMR (250 MHz, DMSO) δ4.58 (d, 2H); 4.36 (t, 2H).

Compound 63 ##STR45## G is

4'-Trifluoromethylbiphenyl-2-carboxylicacid-[2-(4-acetaminophenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide

MS (Cl): 530 (M+H⁺)

¹ H NMR (250 MHz, DMSO) δ4.25 (s, 2H); 1.99 (s, 3H).

Compound 64 ##STR46## G is

4'-Trifluoromethylbiphenyl-2-carboxylicacid-[2-(3-acetylaminophenyl-1,2,3,4,-tetrahydroisoquinolin-6-yl]-amide

MS (Cl): 530 (M+2)

¹ H NMR (400 MHz, DMSO) δ4.25 (s, 2H); 3.44 (t, 2H); 1.99 (s, 3H).

Compound 65 ##STR47## G is

4'-Trifluoromethylbiphenyl-2-carboxylicacid-[2-(2-acetylaminophenyl-1,2,3,4,-tetrahydroisoquinolin-6-yl]-amide

MS (Cl): 530 (M+H⁺)

¹ H NMR (400 MHz, DMSO) δ4.00 (s, 2H); 3.04 (s, 2H); 2.88 (s, 2H); 2.04(s, 3H).

Compound 66 ##STR48## G is

4'-Trifluoromethylbiphenyl-2-carboxylicacid-[2-(4-acetylaminophenyl-1,2,3,4,-tetrahydroisoquinolin-6-yl]-amide

MS (Cl): 536 (M+H⁺)

¹ H NMR (400 MHz, DMSO) δ2.26 (s, 3H).

Compound 67

G is --CH₂)₂ OH

4'-Trifluoromethylbiphenyl-2-carboxylicacid-[2-(2-hydroxyethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide

MS (Cl): 441 (M+H⁺)

EXAMPLE 7

Compounds 68-75

The following compounds were prepared by the procedure of Method Cdescribed hereinabove. The following synthesis is exemplary of theprocedure of Method C.

Compound 68 ##STR49## G is

4'-Trifluoromethylbiphenyl-2-carboxylicacid-[2-(2-oxo-phenylethyl)-1,2,3,4,-tetrahydroisoquinolin-6-yl]-amide

Compound (II) (0.30 gm, 0.76 mmole), 2-bromoacetophenone (0.15 g, 0.76mmole) and potassium carbonate (0.12 gm, 0.83 mmole) were combined in 20mL of acetonitrile and heated to reflux for 1 hr., and then the solventwas evaporated under vacuum. The residue was dissolved in chloroform andwashed with saturated sodium bicarbonate. Purification of the driedorganic layer was accomplished with silica gel chromatography using 50%ethyl acetate in hexane as the eluent.

MS (Cl): 515 (M+H⁺)

The following compounds were synthesized in a manner analogous to thatdescribed hereinabove for Compound 68. Preparative details for Compounds74 and 75, which were synthesized by a minor modification of the abovegeneral method, are found under their respective headings.

Compound 69

G is --CH₂ CONH₂

4'-Trifluoromethylbiphenyl-2-carboxylicacid-(2-carbamoylmethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide

MS (Cl): 454 (M+H⁺)

¹ H NMR (250 MHz, DMSO) δ3.55 (s, 2H); 3.01 (s, 2H); 2.78 (m, 2H); 2.67(m, 2H).

Compound 70

G is --CH₂ COOH

{6-[(4-Trifluoromethylbiphenyl-2-carbonyl)-amino]-3,4-dihydro-1H-isoquinolin-2-yl}-aceticacid

MS (Cl): 455 (M+H⁺)

¹ H NMR (250 MHz, DMSO) δ3.55 (s, 2H); 2.83 (s, 2H); 2.68 (s, 4H).

Compound 71

G is --CH₂ COOCH₃

{6-[(4-Trifluoromethylbiphenyl-2-carbonyl)-amino]-3,4-dihydro-1H-isoquinolin-2-yl}-aceticacid methyl ester

MS (Cl): 469 (M+H⁺)

¹ H NMR (300 MHz, CDCl₃) δ3.75 (s, 3H); 3.72 (s, 2H); 3.40 (s, 2H); 2.85(s, 4H).

Compound 72

G is --CH₂ CON(CH₃)₂

4'-Trifluoromethylbiphenyl-2-carboxylicacid-(2-dimethylcarbamoylmethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide

MS (Cl): 482 (M+H⁺)

¹ H NMR (300 MHz, CDCl₃) δ3.65 (s, 2H); 3.32 (s, 2H); 3.10 (s, 3H); 2.96(s, 3H); 2.81 (m, 2H); 2.77 (m, 2H).

Compound 73 ##STR50## G is

4'-Trifluoromethylbiphenyl-2-carboxylicacid-[2-(2-cyclohexylethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide

MS (Cl): 507 (M+H⁺)

¹ H NMR (250 MHz, DMSO) δ3.44 (s, 2H).

Compound 74

G is --(CH₂)₂ CN

4'-Trifluoromethylbiphenyl-2-carboxylicacid-[2-(2-cyanoethyl)1,2,3,4-tetrahydroisoquinolin-6-yl]-amide

Compound (II) (780 mg, 1.97 mmole), 3-bromopropionitrile (290 mg, 2.17mmole) and 4-dimethylaminopyridine (264 mg, 2.16 mmole) were combined in10 mL of DMF and heated to 70° C. for 72 hrs. The reaction was dilutedwith methylene chloride, washed with water and brine, and then driedover magnesium sulfate. Purification of the residue obtained onevaporation was carried out with silica gel chromatography using agradient of 10-100% ethyl acetate in hexane as the eluent.

MS (Cl): 450 (M+H⁺)

Compound 75 ##STR51## G is

4'-Trifluoromethylbiphenyl-2-carboxylicacid-(2-pyridin-2-yl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide

Compound (II) (0.20 g, 0.50 mmole), 2-bromopyridine (0.16 g, 1.0 mmole)and potassium carbonate (0.14 g, 1.0 mmole) were combined in 5 mL ofchlorobenzene and the resulting mixture was heated to reflux for 48 hrs.The solvent was removed under vacuum and the residue was purified viasilica gel chromatography using 50% ethyl acetate in hexane as theeluent

MS (Cl): 474 (M+H⁺)

¹ H NMR (250 MHz, CDCl₃) δ4.63 (s, 2H); 3.79 (t, 2H); 2.89 (t, 2H).

EXAMPLE 8

Compounds 76 and 77

The following compounds were produced by the procedure of Method Ddescribed hereinabove. The following synthesis is exemplary of theprocedure of Method D.

Compound 76 ##STR52## G is

4'-Trifluoromethylbiphenyl-2-carboxylicacid-[2-(2-pyridin-2-yl-ethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide

Compound (II) (300 mg, 0.76 mmole), 2-vinylpyridine (95 mg, 0.91 mmole)and glacial acetic acid (24 mg, 0.40 mmole) were combined in 15 mL ofmethanol and heated to reflux for 24 hrs. The solvent was removed undervacuum and the residue was purified using silica gel chromatography witha gradient of 0 to 3% methanol in ethyl acetate as the eluent.

MS (Cl): 502 (M+H⁺)

¹ H NMR (250 MHz, CDCl₃) δ3.67 (s, 2H); 3.09 (m, 2H); 2.92 (m, 2H); 2.80(m, 4H).

The following compound was synthesized in a manner analogous to thatdescribed hereinabove for Compound 76.

Compound 77

G is --(CH₂)₂ CON(CH₃)₂

4'-Trifluoromethylbiphenyl-2-carboxylicacid-[2-(2-dimethylcarbamoylethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide

MS (Cl): 496 (M+H⁺)

¹ H NMR (250 MHz, DMSO) δ3.50 (s, 2H); 2.98 (s, 3H); 2.80 (s, 3H).

EXAMPLE 9

Compounds 78-87

The following compounds were produced by the procedure of Method Edescribed hereinabove. The following synthesis is exemplary of theprocedure of Method E.

Compound 78 ##STR53## G is

4'-Trifluoromethylbiphenyl-2-carboxylicacid-{2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-1,2,3,4-tetrahydroisoquinolin-6-yl}-amide

Compound 70 of Example 7 (60 mg, 0.13 mmole), 1-methylpiperazine (22 μL,0.20 mmole) and 1-(3-dimethylaminopropyl-3-ethylcarbodiimidehydrochloride (28 mg, 0.15 mmole) were combined in 4 mL of anhydrousmethylene chloride and stirred at ambient temperature for 15 hrs. Thereaction was diluted with methylene chloride and washed with 1 N NaOHfollowed by brine and then dried over sodium sulfate. The organic layerwas evaporated under vacuum and the residue was purified by silica gelcolumn chromatography using a gradient of 1 to 8% methanol in methylenechloride as the eluent.

MS (Cl): 537 (M+H⁺)

The following compounds were synthesized in a manner analogous to thatdescribed hereinabove for Compound 78.

Compound 79 ##STR54## G is

4'-Trifluoromethylbiphenyl-2-carboxylicacid-[2-(2-oxo-2-pyrrolidin-1-ylethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl-amide

MS (Cl): 508 (M+H⁺)

¹ H NMR (300 MHz, CDCl₃) δ3.67 (s, 2H); 3.50 (s, 4H); 3.28 (s, 2H); 2.81(m, 4H); 1.88 (m, 4H).

Compound 80 ##STR55## G is

4'-Trifluoromethylbiphenyl-2-carboxylicacid-(2-phenylcarbamoylmethyl-1,2,3,4-tetrahydroisquinolin-6-yl)-amide

MS (Cl): 530 (M+H⁺)

¹ H NMR (300 MHz, CDCl₃) δ3.77 (s, 2H); 3.29 (s, 2H); 2.88 (m, 4H).

Compound 81

G is --CH₂ CONHCH₃

4'-Trifluoromethylbiphenyl-2-carboxylicacid-(2-methylcarbamoylmethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide

MS (Cl): 468 (M+H⁺)

¹ H NMR (250 MHz, DMSO) δ3.54 (s, 2H); 3.05 (s, 2H); 2.79 (m, 2H); 2.66(m, 2H); 2.61 (d, 3H).

Compound 82

G is --CH₂ CON(CH₂ CH₃)₂

4'-Trifluoromethylbiphenyl-2-carboxylic acid-(2diethylcarbamoylmethyl-1,2,3,4-tetrahydoisoquinolin-6-yl)-amide

MS (Cl): 510 (M+H⁺)

Compound 83 ##STR56## G is

4'-Trifluoromethylbiphenyl-2-carboxylicacid-(2-cyclopropylcarbamoylmethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide

MS (Cl): 494 (M+H⁺)

¹ H NMR (250 MHz, DMSO) δ3.53 (s, 2H).

Compound 84 ##STR57## G is

4'-Trifluoromethylbiphenyl-2-carboxylicacid-[2-(benzylcarbamoylmethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide

MS (Cl): 544 (M+H⁺)

¹ H NMR (250 MHz, DMSO) δ4.30 (d, 2H); 3.58 (s, 2H); 3.14 (s, 2H); 2.78(m, 2H); 2.68 (m, 2H).

Compound 85 ##STR58## G is

4'-Trifluoromethylbiphenyl-2-carboxylicacid-{2-[2-(3-hydroxypyrrolidin-1-yl)-2-oxoethyl]-1,2,3,4-tetrahydroisoquinolin-6-yl}-amide

MS (Cl): 524 (M+H⁺)

Compound 86 ##STR59## G is

4'-Trifluoromethylbiphenyl-2-carboxylicacid-[2-(2-morpholin-4-yl-2-oxoethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide

MS (Cl): 524 (M+H⁺)

Compound 87 ##STR60## G is

4'-Trifluoromethylbiphenyl-2-carboxylicacid-[2-(2-oxo-2-thiazolidin-3-yl-ethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide

MS (Cl): 526 (M+H⁺)

EXAMPLE 10

Compounds (II') and 88

The following compounds were produced by the procedure of Method Fdescribed hereinabove. For purposes of illustration, a preparation ofcarbonyl compound (II') is also included.

Compound (II')

4'-Trifluoromethylbiphenyl-2-carboxylicacid-[2-(thiophen-2-yl-acetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide

Compound (II) (3.1 g, 7.8 mmole), 2-thiopheneacetic acid (1.14 g, 8.0mmole) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(1.7 g, 8.8 mmole) were stirred in 50 mL of methylene chloride for 12hrs. at ambient temperature. The reaction was diluted with methylenechloride, washed with 1N hydrochloric acid, 1N NaOH, water and brine.Purification of the residue obtained on evaporation was accomplishedwith silica gel chromatography using 50% ethyl acetate in hexanes as theeluent to yield 3.6 g of the title compound as a solid.

Compound 88 ##STR61## G is

4'-Trifluoromethylbiphenyl-2-carboxylicacid-[2-(2-thiophen-2-yl-ethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide

A 200 mg (0.38 mmole) sample of compound (II') and sodium borohydride(45 mg, 1.2 mmole) were combined in 1 mL of pyridine and the mixture washeated to reflux for 18 hrs. The pyridine was removed under vacuum andthe residue was mixed with 10% hydrochloric acid for 20 hrs. at 50° C.The reaction was rendered basic (pH>12) and was extracted with methylenechloride. The organic layer was washed with water and brine and thendried over potassium carbonate. Purification of the residue obtained onevaporation was accomplished with silica gel chromatography using 0.5%methanol in methylene chloride as the eluent

MS (Cl): 507 (M+H⁺)

¹ H NMR (250 MHz, CDCl₃) δ3.65 (s, 2H); 3.11 (t, 2H); 2.79 (m, 6H).

EXAMPLE 11

Compounds 89-93

The following compounds were produced by the procedure of Method Gdescribed hereinabove. The following synthesis is exemplary of theprocedure of Method G.

Compound 89

G is --(CH₂)₂ OCOCH₃

Acetic acid2-{6-[(4'-trifluoromethylbiphenyl-2carbonyl)-amino]-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl ester

Acetyl chloride (100 mg, 1.25 mmole) and 4-dimethylaminopyridine (700mg, 5.7 mmole) were combined in 5 mL of toluene and the mixture wascooled to 0° C. in an ice bath. To this mixture was added a solution ofCompound 67 from Example 6 (500 mg, 1.14 mmole) in 3 mL of methylenechloride. The reaction was allowed to warm to ambient temperature andwas stirred under a nitrogen atmosphere for 2 hrs. The reaction waswashed with 1 N hydrochloric acid, saturated sodium bicarbonate, andbrine and then dried over magnesium sulfate. Purification of the residueobtained on evaporation was accomplished with silica gel chromatographyusing 3% methanol in ethyl acetate as the eluent.

MS (Cl): 483 (M+H⁺)

¹ H NMR (400 MHz, DMSO) δ4.25 (dd, 2H); 3.62 (s, 2H); 2.78 (m, 6H); 2.06(s, 3H).

The following compounds were synthesized in a manner analogous to thatdescribed hereinabove for Compound 89.

Compound 90

G is --(CH₂)₂ OCOC(CH₃)₃

2,2-Dimethylpropionic acid2-{6-[(4'-trifluoromethylbiphenyl-2-carbonyl)-amino}3,4-dihydro-1H-isoquinolin-2-yl}-ethylester

MS (Cl): 525 (M+H⁺)

¹ H NMR (250 MHz, DMSO) δ4.25 (dd, 2H); 3.63 (s, 2H); 2.77 (dd, 6H);1.19 (s, 9H).

Compound 91

G is --(CH₂)₂ OCON(CH₃)₂

Dimethylcarbamic acid2-{6-[4'-trifluoromethylbiphenyl-2-carbonyl)-amino]-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl ester

MS (Cl): 512 (M+H⁺)

¹ H NMR (400 MHz, CDCl₃) δ4.26 (t, 2H); 3.69 (t, 2H); 3.64 (s, 3H); 2.90(s, 3H); 2.79 (m, 4H); 2.70 (t, 2H).

Compound 92

G is --(CH₂)₂ OCOOCH₃

Carbonic acid methyl ester2-{6-[(4'-trifluoromethylbiphenyl-2-carbonyl}-amino]-3,4-dihydro-1H-isoquinolin-2-}-ethylester

MS (Cl): 499 (M+H⁺)

¹ H NMR (400 MHz, CDCl₃) δ4.32 (t, 2H); 3.77 (s, 3H); 3.63 (s, 2H); 2.79(m, 6H).

Compound 93 ##STR62## G is

Benzoic acid2-{6-[(4'-trifluoromethylbiphenyl-2-carbonyl)-amino]-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl ester

MS (Cl): 545 (M+H⁺)

¹ H NMR (400 MHz, CDCl₃) δ4.52 (t, 2H); 3.70 s, 2H); 2.93 (t, 2H); 2.83(s, 4H).

EXAMPLE 12

Compounds 94-105

The following compounds were produced by the procedure of Method Hdescribed hereinabove.

Compound 94

4'-Trifluoromethylbiphenyl-2-carboxylicacid-[2-(2-aminoethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide

An 8.00 g (16.6 mmole) sample of Compound 49 from Example 6 was refluxedin 100 mL of 2N hydrochloric acid for 24 hrs. The reaction was renderedbasic with 1 N NaOH and the mixture was extracted with ethyl acetate.The residue obtained upon evaporation was purified by silica gelchromatography using a gradient of 0-10% methanol in methylene chloridewith 1% ammonium hydroxide as the eluent to furnish 3.5 of the titlecompound.

MS (Cl): 440 (M+H⁺)

¹ H NMR (250 MHz, CDCl₃) δ3.58 (s, 2H); 2.84 (m, 4H); 2.70 (t, 2H); 2.58(t, 2H).

Compound 95

G is --(CH₂)₂ NHS(O)₂ CH₃

4'-Trifluoromethylbiphenyl-2-carboxylicacid-[2-(2-methanesulfonylaminoethyl)-1,2,3,4-tetrahydoisoquinolin-6-yl]-amide

To a 5 mL solution of Compound 94 (250 mg, 0.57 mmole) in methylenechloride previously cooled to 0° C. was added methanesulfonyl chloride(65 mg, 0.57 mmole). The reaction was warned to ambient temperature andstirred for 12 hrs. The reaction was washed with saturated sodiumbicarbonate, extracted with ethyl acetate and dried over magnesiumsulfate. Purification of the residue obtained upon evaporation wasaccomplished with silica gel chromatography using 10% methanol inmethylene chloride with 1% ammonium hydroxide as the eluent.

MS (Cl): 518 (M+H⁺)

¹ H NMR (400 MHz, CDCl₃) δ3.62 (s, 2H); 3.29 (m, 2H); 2.95 (s, 3H); 2.77(m, 6H).

The following compounds were synthesized in a manner analogous to thatdescribed hereinabove for Compound 95.

Compound 96

G is --(CH₂)₂ NHCOCH₂ CH₃

4'-Trifluoromethylbiphenyl-2-carboxylicacid-[2-(2-propionylaminoethyl)1,2,3,4-tetrahydroisoquinolin-6-yl]-amide

MS (Cl): 496 (M+H⁺)

¹ H NMR (400 MHz, DMSO) δ3.70 (s, 2H); 3.42 (dd, 2H); 2.82 (t, 2H); 2.72(t, 2H); 2.64 (t, 2H); 2.17 (q, 2H); 1.12 (t, 3H).

Compound 97

G is --(CH₂)₂ NHCON(CH₃)₂

4-Trifluoromethylbiphenyl-2-carboxylicacid-{2-[2-(3,3-dimethylureido)-ethyl]-1,2,3,4-tetrahydroisoquinolin-6-yl}-amide

MS (Cl): 511 (M+H⁺) ¹ H NMR (400 MHz, CDCl₃) δ3.56 (s, 2H); 3.37 (m,2H); 2.84 (s, 6H); 2.79 (t, 2H); 2.69 (t, 2H); 2.63 (t, 2H).

Compound 98

G is --(CH₂)₂ NHCOOCH₃

(2-{6-[(4'-Trifluoromethylbiphenyl-2-carbonyl)-amino]-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-carbamicacid methyl ester

MS (Cl): 498 (M+H⁺)

¹ H NMR (400 MHz, CDCl₃) δ3.64 (s, 3H); 3.55 (s, 2H); 3.34 (m, 2H); 2.80(t, 2H); 2.69 (t, 2H); 2.61 (t, 2H).

Compound 99

G is --(CH₂)₂ NHCOC(CH₃)₃

4'-Trifluoromethylbiphenyl-2-carboxylicacid-{2-[2-(2,2-dimethylpropionylamino)-ethyl]-1,2,3,4-tetrahydroisoquinolin-6-yl}-amide

MS (Cl): 524 (M+H⁺)

¹ H NMR (400 MHz, CDCl₃) δ3.57 (s, 2H); 3.39 (m, 2H); 2.80 (t, 2H); 2.70(t, 2H); 2.63 (t, 2H); 1.98 (s, 9H).

Compound 100 ##STR63## G is

4'-Trifluoromethylbiphenyl-2-carboxylicacid-[2-(2-benzoylaminoethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide

MS (Cl): 544 (M+H⁺)

¹ H NMR (400 MHz, CDCl₃) δ3.62 (m, 4H); 2.84 (m, 2H); 2.75 (m, 4H).

The following compounds were also synthesized according to the procedurefor Compound 95, except the corresponding acid anydride was substitutedfor the acid halide.

Compound 101

G is --(CH₂)₂ NHS(O)₂ CF₃

4'-Trifluoromethylbiphenyl-2-carboxylicacid-[2-(2-trifluoromethanesulfonylaminoethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide

MS (Cl): 572 (M+H⁺)

¹ H NMR (400 MHz, CDCl₃) δ3.77 (s, 2H); 3.51 (t, 2H); 2.88 (m, 6H).

Compound 102

G is --(CH₂)₂ NHCOCF₃

4'-Trifluoromethylbiphenyl-2-carboxylicacid-{2-[2-(2,2,2-trifluoroacetylamino)-ethyl]-1,2,3,4-tetrahydroisoquinolin-6-yl}-amide

MS (Cl): 536 (M+H⁺)

¹ H NMR (400 MHz, CDCl₃) δ3.61 (s, 2H); 3.51 (dd, 2H); 2.82 (t, 2H);2.73 (m, 4H).

Compound 103

G is --(CH₂)₂ NHCHO

4'-Trifluoromethylbiphenyl-2-carboxylicacid-[2-(2-formylaminoethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide

Compound 94 (250 mg, 0.57 mmole) was combined with formic acid (66 mg,1.4 mmole) and heated to reflux for 30 min. Purification of the residueobtained on evaporation was accomplished with silica gel chromatographyusing 10% methanol in methylene chloride with 1% ammonium hydroxide asthe eluent

MS (Cl): 468 (M+H⁺)

¹ H NMR (400 MHz, CDCl₃) δ3.59 (s, 2H); 3.48 (m, 2H); 2.83 (m, 2H); 2.742H); 2.67 (t, 2H).

Compound 104

G is --(CH₂)₂ NHCONH₂

4'-Trifluoromethylbiphenyl-2-carboxylicacid-[2-(2-ureidoethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide

Compound 94 (250 mg, 0.57 mmole) was combined with1,1'-carbonyldiimidazole in 6 mL of methylene chloride and stirred for 4hrs. The reaction was cooled to 0° C. in an ice bath and gaseous ammoniawas perfused into the solution. The reaction was then stirred at ambienttemperture for 12 hrs. Purification of the residue obtained onevaporation was accomplished with silica gel chromatography using 10%methanol in methylene chloride with 1% ammonium hydroxide as the eluent.

MS (Cl): 483 (M+H⁺)

¹ H NMR (400 MHz, CDCl₃) δ3.62 (m, 1H); 3.58 (s, 2H); 3.35 (m, 1H); 2.82(m, 2H); 2.76 (m, 2H); 2.65 (m, 2H).

The following compound was synthesized in a manner analogous to thatdescribed for Compound 104.

Compound 105

G is --(CH₂)₂ NHCONHCH₃

4'-Trifluoromethylbiphenyl-2-carboxylicacid-{2-[2-(3-methylureido)-ethyl]-1,2,3,4-tetrahydroisoquinolin-6-yl}-amide

MS (Cl): 497 (M+H⁺)

¹ H NMR (400 MHz, CDCl₃) δ3.59 (s, 2H); 3.35 (s, 2H); 2.82 (m, 2H); 2.74(t, 2H); 2.70 (s, 3H); 2.65 (t, 2H).

EXAMPLE 13

Compounds 106-110

The following compounds were produced by the procedure of Method Idescribed hereinabove.

Compound 106 ##STR64##

4'-Trifluoromethylbiphenyl-2-carboxylicacid-(2-piperidin-4-yl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide

A 20 g (415 mmole) sample of Compound 61 from Example 6 was combinedwith palladium hydroxide on carbon (6.1 g) in 260 mL of methanol and 550mL of THF. Ammonium formate (26 g, 415 mmole) was added and the reactionmixture was heated to 60° C. for 4 hrs. The reaction was filtered andthe filter cake was washed with THF followed by methanol. The solutionwas concentrated and 40 mL of 1N NaOH and 150 mL of water were added.The mixture was stirred for 2 hrs. and filtered to give 15 g of thetitle compound.

The following compound was synthesized by functionalizing Compound 106in the reductive amination procedure of Method A.

Compound 107 ##STR65## G is

4'-Trifluoromethylbiphenyl-2-carboxylicacid-[2-(1-methylpiperidine-4-yl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide

MS (Cl): 494 (M+H⁺)

¹ H NMR (250 MHz, CDCl₃) δ3.70 (s, 2H); 2.95 (d, 2H); 2.79 (s, 4H); 2.29(s, 3H).

The following compound was synthesized by functionalizing Compound 106in the amidation procedure of Method H.

Compound 108 ##STR66## G is

4'-Trifluoromethylbiphenyl-2-carboxylicacid-[2-(1-acetylpiperidin-4-yl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide

MS (Cl): 522 (M+H⁺)

¹ H NMR (250 MHz, CDCl₃) δ3.72 (s, 2H); 2.81 (s, 4H); 2.10 (s, 3H).

Compound 109 ##STR67## G is

4'-Trifluoromethylbiphenyl-2-carboxylicacid-[2-(1-trifluoroacetylpiperidin-4-yl)-1,2,3,4-tetrahydroisoquiolin-6-yl]-amide

MS (Cl): 576 (M+H⁺)

¹ H NMR (250 MHz, CDCl₃) δ3.72 (s, 2H); 3.17 (t, 1H); 2.83 (m, 6H).

Compound 110 ##STR68## G is

4'-Trifluoromethylbiphenyl-2-carboxylicacid-2-(1-benzoylpiperidin-4-yl)-1,2,3,4-tetrahydoisoquinolin-6-yl]-amide

MS (Cl): 584 (M+H⁺)

¹ H NMR (250 MHz, CDCl₃) δ3.75 (s, 2H); 2.83 (s, 6H).

EXAMPLE 14

Compound 111

The following compound was synthesized by the procedure of Method Jdescribed hereinabove. Compound 111 ##STR69## G is

4'-Trifluoromethylbiphenyl-2-carboxylicacid-{2-[2-(2H-[1,2,4-]triazol-3-yl)ethyl]-1,2,3,4-tetrahydroisoquinolin6-yl}-amide

A 300 mg (0.67 mmole) sample of Compound 74 and sodium methoxide (3.6mg, 0.067 mmole) were combined in 2 mL of methanol and stirred atambient temperature for 5 hrs. Formic hydrazine (40 mg, 0.67 mmole) in 1mL of methanol was added and the reaction was stirred at ambienttemperature for 12 hrs., followed by reflux for 48 hrs. The reaction wasconcentrated and diluted with chloroform. The organic layer was washedwith saturated sodium bicarbonate, brine and dried over sodium sulfate.Purification was accomplished with silica gel chromatography using agradient of 2-16% ethanol in chloroform as the eluent

MS (Cl): 492 (M+H⁺)

We claim:
 1. A compound of the formula ##STR70## or the stereoisomers,pharmaceutically acceptable salts and hydrates thereof, wherein G isselected from:(a) a phenyl or heterocyclic ring wherein saidheterocyclic ring contains a total of from 3 to 14 ring atoms, whereinsaid heterocyclic ring incorporates a total of from 1 to 4 ringheteroatoms selected independently from oxygen, nitrogen, and sulfur,wherein the individual rings of said heterocyclic ring may beindependently saturated, partially saturated or aromatic, and whereineach of said phenyl or heterocyclic rings may have optionally from 1 to4 substituents selected independently from halogen, hydroxy, cyano,nitro, oxo, thioxo, aminosulfonyl, phenyl, phenoxy, phenylthio, benzyl,benzoyl, benzyloxy, (C₁ -C₁₀)alkyl, (C₁ -C₄)perfluoroalkyl, (C₁-C₁₀)alkoxy, (C₁ -C₄)perfluoroalkoxy, (C₁ -C₁₀)alkoxycarbonyl, (C₁-C₁₀)alkylthio, (C₁ -C₁₀)alkylamino, di(C₁ -C₁₀)alkylamino, (C₁-C₁₀)alkylaminocarbonyl, di(C₁ -C₁₀)alkylaminocarbonyl, (C₁ -C₁₀)acyl,(C₁ -C₁₀)perfluoroacyl, (C₁ -C₁₀)acyloxy, (C₁ -C₆)acylamino and (C₁-C₆)perfluoroacylamino; (b) --CH₂ CN, ##STR71## (d) (C₂ -C₁₂)alkyl or(C₂ -C₁₂)perfluoroalkyl wherein each of said (C₂ -C₁₂)alkyl and (C₂-C₁₂)perfluoroalkyl is substituted optionally with from 1-3 substituentsselected independently from:(1) phenyl, halogen, nitro, cyano, hydroxy,--NR¹ R², --OCOR³, (C₁ -C₄)alkoxy, (C₁ -C₄)perfluoroalkoxy, (C₁-C₄)thioalkoxy or (C₁ -C₄)perfluorothioalkoxy, where R¹ and R² in thedefinition of --NR¹ R² are each selected independently from hydrogen,formyl, phenyl, benzyl, benzoyl, (C₃ -C₈)cycloalkyl, (C₃-C₈)cycloalkenyl, (C₁ -C₄)alkyl, (C₁ -C₄)perfluoroalkyl, (C₁-C₁₀)alkoxycarbonyl, (C₁ -C₆)acyl, (C₁ -C₆)perfluoroacyl, aminocarbonyl,(C₁ -C₁₀)alkylaminocarbonyl, di(C₁ -C₁₀)alkylaminocarbonyl,aminosulfonyl, (C₁ -C₄)alkylaminosulfonyl, di(C₁ -C₄)alkylaminosulfonyl,(C₁ -C₄)perfluoroalkylaminosulfonyl, (C₁-C₄)perfluoroalkylaminosulfonyl, (C₁ -C₄)alkylsulfonyl, and(C₁-C₄)perfluoroalkylsulfonyl, or where R¹ and R², taken together with thenitrogen atom to which they are attached, form a saturated,partially-saturated or aromatic heterocyclic ring, wherein saidheterocyclic ring contains a total of from 3 to 14 ring atoms andincorporates optionally an additional 1 to 4 ring heteroatoms selectedindependently from oxygen, nitrogen and sulfur, wherein saidheterocyclic ring may have optionally from 1 to 4 substituents selectedindependently from halogen, hydroxy, cyano, nitro, oxo, thioxo,aminosulfonyl, phenyl, phenoxy, phenylthio, benzyl, benzoyl, benzyloxy,(C₁ -C₁₀)alkyl, (C₁ -C₄)perfluoroalkyl, (C₁ -C₁₀)alkoxy, (C₁-C₄)perfluoroalkoxy, (C₁ -C₁₀)alkoxycarbonyl, (C₁ -C₁₀)alkylthio, (C₁-C₁₀)alkylamino, di(C₁ -C₁₀)alkylamino, (C₁ -C₁₀)alkylaminocarbonyl,di(C₁ -C₁₀)alkylaminocarbonyl, (C₁ -C₁₀)acyl, (C₁ -C₁₀)perfluoroacyl,(C₁ -C₁₀)acylamino, and (C₁ -C₁₀)acyloxy, where R³ in the definition of--OCOR³ is selected from --NR¹ R², phenyl, (C₁ -C₁₀)alkyl, (C₁-C₄)perfluoroalkyl, (C₁ -C₆)alkoxy and (C₁ -C₆)perfluoroalkoxy, (2) (C₃-C₈)cycloalkyl or (C₃ -C₈)cycloalkenyl wherein each of said (C₃-C₈)cycloalkyl and (C₃ -C₈)cycloalkenyl may have optionally from 1 to 4substituents selected independently from halogen, hydroxy, cyano, nitro,oxo, thioxo, aminosulfonyl, phenyl, phenoxy, phenylthio, benzyl,benzoyl, benzyloxy, (C₁ -C₁₀)alkyl, (C₁ -C₄)perfluoroalkyl, (C₁-C₁₀)alkoxy, (C₁ -C₄)perfluoroalkoxy, (C₁ -C₁₀)alkoxycarbonyl, (C₁-C₁₀)alkylthio, (C₁ -C₁₀)alkylamino, di(C₁ -C₁₀)alkylamino, (C₁-C₁₀)alkylaminocarbonyl, di(C₁ -C₁₀)alkylaminocarbonyl, (C₁ -C₁₀)acyl,(C₁ -C₁₀)perfluoroacyl, (C₁ -C₁₀)acylamino, (C₁ -C₁₀)perfluoroacylamino,(C₁ -C₁₀)acyloxy, and (3) a saturated, partially-saturated or aromaticheterocyclic ring containing a total of from 3 to 14 ring atoms, whereinsaid heterocyclic ring incorporates a total of from 1 to 4 ringheteroatoms selected independently from oxygen, nitrogen and sulfur,wherein said heterocyclic ring may have optionally from 1 to 4substituents selected independently from halogen, hydroxy, cyano, nitro,oxo, thioxo, aminosulfonyl, phenyl, phenoxy, phenylthio, benzyl,benzoyl, benzyloxy, (C₁ -C₁₀)alkyl, (C₁ -C₄)perfluoroalkyl, (C₁-C₁₀)alkoxy, (C₁ -C₄)perfluoroalkoxy, (C₁ -C₁₀)alkoxycarbonyl, (C₁-C₁₀)alkylthio, (C₁ -C₁₀)alkylamino, di(C₁ -C₁₀)alkylamino, (C₁-C₁₀)alkylaminocarbonyl, di(C₁ -C₁₀)alkylaminocarbonyl, (C₁ -C₁₀)acyl,(C₁ -C₁₀)perfluoroacyl, (C₁ -C₁₀)acylamino, (C₁ -C₁₀)perfluoroacylamino,(C₁ -C₁₀)acyloxy, provided that (C₂ -C₁₂)alkyl does not includeunsubstituted allyl; (e) (C₃ -C₈)cycloalkyl or (C₃ -C₈)cycloalkenylwherein each of said (C₃ -C₈)cycloalkyl and (C₃ -C₈)cycloalkenyl mayhave optionally from 1 to 4 substituents selected independently fromhalogen, hydroxy, cyano, nitro, oxo, thioxo, aminosulfonyl, phenyl,phenoxy, phenylthio, benzyl, benzoyl, benzyloxy, (C₁ -C₁₀)alkyl, (C₁-C₄)perfluoroalkyl, (C₁ -C₁₀)alkoxy, (C₁ -C₄)perfluoroalkoxy, (C₁-C₁₀)alkoxycarbonyl, (C₁ -C₁₀)alkylthio, (C₁ -C₁₀)alkylamino, di(C₁-C₁₀)alkylamino, (C₁ -C₁₀)alkylaminocarbonyl, di(C₁-C₁₀)alkylaminocarbonyl, (C₁ -C₁₀)acyl, (C₁ -C₁₀)perfluoroacyl, (C₁-C₁₀)acylamino, (C₁ -C₁₀)perfluoroacylamino, (C₁ -C₁₀)acyloxy; and (f)--(CH₂)_(n) COR⁴ where R⁴ in the definition of --(CH₂)_(n) COR⁴ isselected from hydroxy, phenyl, --NR¹ R², (C₁ -C₄)alkyl, (C₁-C₄)perfluoroalkyl, (C₁ -C₄)alkoxy, (C₁ -C₄)perfluoroalkoxy, (C₃-C₈)cycloalkyl, and (C₃ -C₈)cycloalkenyl,where n is an integer from 1 to4.
 2. A compound as claimed in claim 1 and the stereoisomers,pharmaceutically acceptable salts and hydrates thereof, wherein G isselected from:(a) a phenyl or heterocyclic ring wherein saidheterocyclic ring contains a total of from 3 to 7 ring atoms, whereinsaid heterocyclic ring incorporates a total of from 1 to 4 ringheteroatoms selected independently from oxygen, nitrogen, and sulfur,wherein said heterocyclic ring may be saturated, partially saturated oraromatic, and wherein each of said phenyl or heterocyclic rings may eachhave optionally from 1 to 4 substituents selected independently fromhalogen, hydroxy, phenyl, benzyl, benzoyl, benzyloxy, (C₁ -C₁₀)alkyl,(C₁ -C₄)perfluoroalkyl, (C₁ -C₁₀)alkoxy, (C₁ -C₄)perfluoroalkoxy, (C₁-C₁₀)alkoxycarbonyl, (C₁ -C₁₀)alkylthio, (C₁ -C₁₀)alkylamino, di(C₁-C₁₀)alkylamino, (C₁ -C₁₀)alkylaminocarbonyl, di(C₁-C₁₀)alkylaminocarbonyl, (C₁ -C₁₀)acyl, (C₁ -C₁₀)perfluoroacyl, (C₁-C₆)acylamino, (C₁ -C₆)perfluoroacylamino, (C₁ -C₁₀)acyloxy; (b) (C₂-C₁₂)alkyl wherein said (C₂ -C₁₂)alkyl is substituted optionally withfrom 1-3 substituents selected independently from:(1) phenyl, halogen,cyano, hydroxy, --NR¹ R², --OCOR³, (C₁ -C₄)alkoxy, or (C₁-C₄)perfluoroalkoxy, where R³ in the definition of --OCOR³ is selectedfrom --NR¹ R², (C₁ -C₄)alkyl and (C₁ -C₄)perfluoroalkyl, (2) (C₃-C₆)cycloalkyl or (C₃ -C₆)cycloalkenyl wherein each of said (C₃-C₆)cycloalkyl and (C₃ -C₆)cycloalkenyl may optionally have from 1 to 4substituents selected independently from hydroxy, (C₁ -C₄)alkyl, (C₁-C₄)alkoxy, and (C₁ -C₄)alkoxycarbonyl, and (3) a saturated,partially-saturated or aromatic heterocyclic ring containing a total offrom 3 to 6 ring atoms, wherein said heterocyclic ring incorporates atotal of from 1 to 4 ring heteroatoms selected independently fromoxygen, nitrogen and sulfur, wherein said heterocyclic ring may haveoptionally from 1 to 4 substituents selected independently from halogen,hydroxy, phenyl, benzyl, benzoyl, benzyloxy, (C₁ -C₁₀)alkyl, (C₁-C₄)perfluoroalkyl, (C₁ -C₁₀)alkoxy, (C₁ -C₁₀)alkoxycarbonyl, (C₁-C₁₀)alkylthio, (C₁ -C₁₀)alkylamino, di(C₁ -C₁₀)alkylamino, (C₁-C₁₀)alkylaminocarbonyl, di(C₁ -C₁₀)alkylaminocarbonyl, (C₁-C₄)perfluoroalkoxy, (C₁ -C₁₀)acyl, (C₁ -C₁₀)acylamino, (C₁-C₁₀)perfluoroacylamino, (C₁ -C₁₀)acyloxy, provided that (C₂ -C₁₂)alkyldoes not include unsubstituted allyl; (c) (C₃ -C₆)cycloalkyl or (C₃-C₆)cycloalkenyl wherein each of said (C₃ -C₆)cycloalkyl and (C₃-C₆)cycloalkenyl may have optionally from 1 to 4 substituents selectedindependently from hydroxy, (C₁ -C₄)alkyl, (C₁ -C₄)alkoxy, (C₁-C₁₀)acylamino, (C₁ -C₁₀)perfluoroacylamino and (C₁ -C₄)alkoxycarbonyl;and (d) --(CH₂)_(n) COR⁴, where R⁴ in the definition of --(CH₂)_(n) COR⁴is selected from hydroxy, phenyl, --NR¹ R², (C₁ -C₄)alkyl, (C₁-C₄)perfluoroalkyl, (C₁ -C₄)alkoxy, (C₁ -C₄)perfluoroalkoxy, (C₃-C₆)cycloalkyl, and (C₃ -C₆)cycloalkenyl,where n is an integer from 1 to4.
 3. A compound as claimed in claim 2, and the stereoisomers,pharmaceutically acceptable salts and hydrates thereof, wherein G is (C₂-C₁₂)alkyl, wherein said (C₂ -C₁₂)alkyl is substituted optionally with agroup selected from phenyl, halogen, cyano, hydroxy, (C₁ -C₄)alkoxy, ora saturated, partially-saturated or aromatic heterocyclic ring selectedfrom thienyl, pyrazolyl, pyrrolidinyl, pyrrolyl, furanyl, thiazolyl,isoxazolyl, imidazolyl, triazolyl, tetrahydropyranyl, pyridyl, andpyrimidyl, wherein each of said heterocyclic rings may have optionallyfrom 1 to 3 substitutents selected independently from halogen, (C₁-C₄)acyl, (C₁ -C₄)perfluoroacyl, (C₁ -C₄)alkyl, (C₁ -C₄)perfluoroalkyl,(C₁ -C₄)alkoxy, (C₁ -C₄)alkylaminocarbonyl, and (C₁-C₄)acylamino,provided that (C₂ -C₁₂)alkyl does not includeunsubstituted allyl.
 4. A compound as claimed in claim 2, and thestereoisomers, pharmaceutically acceptable salts and hydrates thereof,wherein G is --(CH₂)_(n) NR¹ R² and n is an integer from 2 to
 4. 5. Acompound as claimed in claim 2, and the stereoisomers, pharmaceuticallyacceptable salts and hydrates thereof, wherein G is --(CH₂)_(n) COR⁴ andn is 1 or
 2. 6. The compound of claim 2, wherein G is --(CH₂)₂ OCOCH₃.7. The compound of claim 2, wherein G is --(CH₂)₂ OCON(CH₃)₂.
 8. Thecompound of claim 2, wherein G is ##STR72##
 9. The compound of claim 2,wherein G is
 10. The compound of claim 3, wherein G is --(CH₂)₄ CH₃. 11.The compound of claim 3, wherein G is --(CH₂)₂ OCH₃.
 12. The compound ofclaim 3, wherein G is --(CH₂)₂ OCH₂ CH₃.
 13. The compound of claim 3,wherein G is --(CH₂)₃ OCH₃.
 14. The compound of claim 3, wherein G is--(CH₂)₂ CN.
 15. The compound of claim 3, wherein G is
 16. The compoundof claim 3, wherein G is
 17. The compound of claim 3, wherein G is 18.The compound of claim 3, wherein G is
 19. The compound of claim 3,wherein G is
 20. The compound of claim 4, wherein G is --(CH₂)₂ NHS(O)₂CH₃.
 21. The compound of claim 4, wherein G is --(CH₂)₂ NHCHO.
 22. Thecompound of claim 4, wherein G is --(CH₂)₂ NHCOCH₂ CH₃.
 23. The compoundof claim 4, wherein G is --(CH₂)₂ NHCOCF₃.
 24. The compound of claim 4,wherein G is --(CH₂)₂ NHCONHCH₃.
 25. The compound of claim 4, wherein Gis --(CH₂)₂ NHCOOCH₃.
 26. The compound of claim 4, wherein G is --(CH₂)₂NHCOCH₃.
 27. The compound of claim 4, wherein G is --(CH₂)₂ NH₂.
 28. Thecompound of claim 5, wherein G is --CH₂ CON(CH₃)₂.
 29. The compound ofclaim 5, wherein G is --CH₂ CON(CH₂ CH₃)₂.
 30. The compound of claim 5,wherein G is --(CH₂)₂ CON(CH₃)₂.
 31. The compound of claim 5, wherein Gis --CH₂ COOH.
 32. A method for inhibiting or decreasing Apo B secretionin a mammal in need thereof which method comprises the administration ofan Apo B secretion inhibiting or decreasing amount of a compound ofclaim 1 or a stereoisomer, pharmaceutically acceptable salt or hydratethereof.
 33. A method for the treatment of a condition selected fromatherosclerosis, pancreatitis, obesity, hypercholesterolemia,hypertriglyceridemia, hyperlipidemia or diabetes which method comprisesadministering to a mammal in need of such treatment a therapeuticallyeffective amount of a compound of claim 1 or a stereoisomer,pharmaceutically acceptable salt or hydrate thereof.
 34. A method asclaimed in claim 33 wherein said condition is selected fromhypercholesterolemia, hypertriglyceridemia, or hyperlipidemia.
 35. Amethod as claimed in claim 34 wherein said condition ishypercholesterolemia.
 36. A method as claimed in claim 34 wherein saidcondition is hypertriglyceridemia.
 37. A method as claimed in claim 34wherein said condition is hyperlipidemia.
 38. A method as claimed inclaim 33 wherein said condition is selected from atherosclerosis,obesity, or diabetes.
 39. A method as claimed in claim 38 wherein saidcondition is atherosclerosis.
 40. A method as claimed in claim 38wherein said condition is obesity.
 41. A method as claimed in claim 38wherein said condition is diabetes.
 42. A pharmaceutical compositionwhich comprises a therapeutically effective amount of a compound ofclaim 1 or a stereoisomer, pharmaceutically acceptable salt or hydratethereof in combination with a pharmaceutically-acceptable carrier ordiluent.
 43. A pharmaceutical composition for the treatment of acondition selected from atherosclerosis, pancreatitis, obesity,hypercholesterolemia, hypertriglyceridemia, hyperlipidemia or diabetesin a mammal which comprises a therapeutically effective amount of acompound of claim 1 or the stereoisomer, pharmaceutically acceptablesalt or hydrate thereof in combination with a pharmaceuticallyacceptable carrier or diluent.
 44. A pharmaceutical compositioncomprising: a. a therapeutically effective amount of a first compound,wherein said first compound is a compound of claim 1 or a stereoisomer,pharmaceutically acceptable salt or hydrate thereof;b. a therapeuticallyeffective amount of a second compound, wherein said second compound isselected from a cholesterol absorption inhibitor, a CETP inhibitor, anHMG-CoA reductase inhibitor, an HMG-CoA synthase inhibitor, an inhibitorof HMG-CoA reductase gene expression, niacin, an antioxidant, an ACATinhibitor or a squalene synthetase inhibitor; and c. a pharmaceuticallyacceptable carrier or diluent.
 45. A pharmaceutical composition asclaimed in claim 44 wherein said second compound is selected fromlovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin orrivastatin.
 46. A pharmaceutical composition as claimed in claim 45wherein said second compound is atorvastatin.
 47. A method for thetreatment of a condition selected from atherosclerosis, pancreatitis,obesity, hypercholesterolemia, hypertriglyceridemia, hyperlipidemia ordiabetes which method comprises administering to a mammal in need ofsuch treatment:a. a therapeutically effective amount of a firstcompound, wherein said first compound is a compound of claim 1 or astereoisomer, pharmaceutically acceptable salt or hydrate thereof; andb. a therapeutically effective amount of a second compound, wherein saidsecond compound is selected from a cholesterol absorption inhibitor, aCETP inhibitor, an HMG-CoA reductase inhibitor, an HMG-CoA synthaseinhibitor, an inhibitor of HMG-CoA reductase gene expression, niacin, anantioxidant, an ACAT inhibitor or a squalene synthetase inhibitor.
 48. Amethod as claimed in claim 47 wherein said second compound is selectedfrom lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin orrivastatin.
 49. A method as claimed in claim 48 wherein said secondcompound is atorvastatin.
 50. A compound as claimed in claim 1, whereinsaid compound is selectedfrom:{6[(4'-trifluoromethylbiphenyl-2-carbonyl)-amino]-3,4-dihydro-1H-isoquinolin-2-yl}-aceticacid, 4'-trifluoromethylbiphenyl-2-carboxylicacid-(n-pentyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide,4'-trifluoromethylbiphenyl-2-carboxylicacid-[2-(3-methoxypropyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide,4'-trifluoromethylbiphenyl-2-carboxylicacid-[2-(2-methoxyethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide,4'-trifluoromethylbiphenyl-2-carboxylicacid-[2-(2-ethoxyethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide,4'-trifluoromethyl-biphenyl-2-carboxylicacid-[2-(2-cyanoethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide, aceticacid2-{6-[(4'-trifluoromethylbiphenyl-2-carbonyl)-amino]-3,4-dihydro-1H-isoquinolin-2-yl}-ethylester, and dimethylcarbamic acid2-{6-[(4'-trifluoromethylbiphenyl-2-carbonyl)-amino]-3,4-dihydro-1H-isoquinolin-2-yl}-ethylester.
 51. A compound as claimed in claim 1, wherein said compound isselected from:4'-trifluoromethylbiphenyl-2-carboxylicacid-[2-(2-aminoethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide4'-trifluoromethylbiphenyl-2-carboxylicacid-[2-(2-acetylaminoethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide,4'-trifluoromethyl-biphenyl-2-carboxylicacid-[2-(2-dimethylcarbamoylethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide,4'-trifluoromethylbiphenyl-2-carboxylicacid-(2-dimethylcarbamoylmethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide,4'-trifluoromethylbiphenyl-2-carboxylicacid-(2-diethylcarbamoylmethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide,4'-trifluoromethylbiphenyl-2-carboxylicacid-[2-(2-methanesulfonylaminoethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide,4'-trifluoromethylbiphenyl-2-carboxylicacid-{2-[2-(2,2,2-trifluoroacetylamino)-ethyl]-1,2,3,4-tetrahydroisoquinolin-6-yl}-amide,4'-trifluoromethylbiphenyl-2-carboxylicacid-[2-(2-propionylaminoethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide,(2-{6-[4'-trifluoromethylbiphenyl-2-carbonyl)amino]-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-carbamicacid methyl ester, ' -trifluoromethylbiphenyl-2-carboxylicacid-[2-(2-formylaminoethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide,and 4'-trifluoromethylbiphenyl-2-carboxylicacid-{2-[2-(3-methylureido)-ethyl]-1,2,3,4-tetrahydroisoquinolin-6-yl}amide.52. A compound as claimed in claim 1, wherein said compound is selectedfrom:4'-trifluoromethylbiphenyl-2-carboxylicacid{2-[2-(1-methyl-1H-pyrrol-2-yl)ethyl]-1,2,3,4-tetrahydroisoquinolin-6-yl}amide,4'-trifluoromethylbiphenyl-2-carboxylicacid-{2-[2-(2H-[1,2,4]triazol-3-yl-ethyl]-1,2,3,4-tetrahydroisoquinolin-6-yl}-amide,4'-trifluoromethylbiphenyl-2-carboxylicacid-[2-(2,2-diphenylethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide,4'-trifluoromethylbiphenyl-2-carboxylicacid-[2-(2-pyridin-2-yl-ethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide,4'-trifluoromethylbiphenyl-2-carboxylicacid-(2-phenylethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide,4'-trifluoromethylbiphenyl-2-carboxylicacid-(2-piperidin-4-yl-1,2,3,4-tetrahydroisoquinolin-6-yl)amide, and4'-trifluoromethylbiphenyl-2-carboxylicacid-[2-(1-trifluoromethylacetyl-piperidin-4-yl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide.53. A process for the preparation of a compound having the structuralformula ##STR73## which process comprises the steps of: (a) cyclizing adiacid of the structural formula ##STR74## or an activated form thereof,with benzylamine to provide a dione derivative of structural formula##STR75## (b) reducing the product of Step (a) to provide anisoquinoline derivative of structural formula ##STR76## (c) reducing theproduct of Step (b) to provide an amino derivative of structural formula##STR77## (d) coupling the product of Step (c) with the compound4'-trifluoromethylbiphenyl-2-carboxylic acid, or an activated formthereof to provide an amide derivative of structural formula ##STR78##(e) deprotecting the amide derivative of Step (d) to provide said aminoderivative of structural formula ##STR79## (f) isolating the aminoderivative of Step (e) in the free base form or an acid addition saltthereof.
 54. A process for the preparation of a compound having thestructural formula ##STR80## which process comprises the steps of: (a)deprotecting an amide derivative of the structural formula ##STR81## toprovide said amino derivative of structural formula ##STR82## (b)isolating the amino derivative of Step (a) in the free base form or anadd addition salt thereof.
 55. The tosylate acid addition salt of thecompound ##STR83##
 56. A compound having the structural formula or anacid addition salt thereof, wherein R is selected from --NO₂, and --NH₂.